Disclosure
Thrombosis is a naturally occurring physiologic process. Under normal circumstances, a physiologic balance is present between factors that promote and retard coagulation. A disturbance in this equilibrium may result in the coagulation process occurring at an inopportune time or location or in an excessive manor. Alternatively, failure of the normal coagulation mechanisms may lead to hemorrhage. Virchow triad More than 100 years ago, Virchow described a triad of factors of venous stasis, endothelial damage, and a hypercoagulable state that are associated with the equilibrium process. Venous stasis can occur as a result of anything that slows or obstructs the flow of venous blood. This results in an increase in viscosity and the formation of microthrombi, which are not washed away by fluid movement; the thrombus that forms may then grow and propagate. Endothelial (intimal) damage in the blood vessel may be intrinsic or secondary to external trauma. It may result from accidental injury or surgical insult. A hypercoagulable state can occur due to a biochemical imbalance between circulating factors. This may result from an increase in circulating tissue activation factor, combined with a decrease in circulating plasma antithrombin and fibrinolysins. The Virchow triad can be summarized as follows:
Venous thrombi generally form in regions of stasis composed of red blood cells embedded in a mesh of fibrin strands and platelets, usually in response to a hypercoagulable state (see Image 1). In contrast, arterial thrombi usually occur in vessels that have a higher pressure gradient and flow rate. Arterial thrombi are composed mainly of platelet aggregates with relatively few fibrin strands, usually as a result of platelet reaction to intimal vessel damage. Thrombi, which occur in the proximal veins of the lower extremities, may break free and travel to the pulmonary vasculature where, if they are large enough, they can cause a fatal pulmonary embolism (PE) (see Image 2). The coagulation cascade For the most part, the coagulation mechanism consists of a series of self-regulating steps that result in the production of a fibrin clot. These steps are controlled by a number of relatively inactive cofactors or zymogens, which, when activated, promote or accelerate the clotting process. These reactions usually occur at the phospholipid surface of platelets, endothelial cells, or macrophages. Generally, the initiation of the coagulation process can be divided into 2 distinct pathways, an intrinsic system and an extrinsic system (see Image 3). The extrinsic system operates as the result of activation by tissue lipoprotein, usually released as the result of some mechanical injury or trauma. The intrinsic system usually involves circulating plasma factors. Both of these pathways come together at the level of factor X, which is activated to form factor Xa. This in turn promotes the conversion of prothrombin to thrombin (factor II). This is the key step in clot formation, for active thrombin is necessary for the transformation of fibrinogen to a fibrin clot. Once a fibrin clot is formed and has performed its function of hemostasis, mechanisms exist in the body to restore the normal blood flow by lysing the fibrin deposit. Circulating fibrinolysins perform this function. Plasmin digests fibrin and also inactivates clotting factors V and VIII and fibrinogen. Three naturally occurring anticoagulant mechanisms exist to prevent inadvertent activation of the clotting process. These include the heparin-ATIII, protein C and thrombomodulin protein S, and the tissue factor inhibition pathways. When trauma occurs, or when surgery is performed, circulating ATIII is decreased. This has the effect of potentiating the coagulation process. Studies have demonstrated that levels of circulating ATIII is decreased more, and stay reduced longer, after total hip replacement (THR) than after general surgical cases (see Image 4). Furthermore, it has been demonstrated that patients who have positive venograms postoperatively tend to be those in whom circulating levels of ATIII are diminished (see Image 5).
The nature of orthopedic illnesses and diseases, trauma, and surgical repair or replacement of hip and knee joints predisposes patients to the occurrence of venous thromboembolic (VTE) disease. These complications are predictable and are the result of alterations of the natural equilibrium mechanisms in various disease states. An estimated 300,000-600,000 individuals are hospitalized annually in the United States for deep venous thrombosis (DVT) disease. This is especially significant, as up to two thirds of cases of DVT disease remain silent and do not come to medical attention. The autopsy rate in the United States has decreased significantly in past decades, and, therefore, an accurate estimate of deaths from PE is difficult to obtain. An analysis of deaths from VTE in 11600 patients undergoing hip and knee replacement between 1976 and 1985 showed a 17-fold increase within 3 months of the surgery compared with the incidence for the rest of the year. In a study by David Warwick, MD, the death rate from PE was 0.34% in 1162 patients after THR with no prophylaxis. In a Scandinavian study by Bergqvist, PE was found in 23.6% of 1274 patients. PE was believed to be the major causative factor in death in 6.4%. In the United States, this rate would translate to approximately 50,000-100,000 deaths annually due to PE. Similar to DVT, most cases of PE remain silent and clinically go undetected or undiagnosed. Thirty percent of patients presenting with acute PE had no prior symptoms Untreated general surgical patients have a postoperative risk of DVT of 19-25% depending on the method used for diagnosis (see Table 1). Table 1. VTE risk in surgical patients
The fibrinogen uptake test (FUT) is the most sensitive study, followed by venography. Although these methods can demonstrate thrombi, the clinical significance of the results is not always clear. The occurrence of proximal DVT is 7% and is more important from the standpoint of adverse consequences for the patient. The occurrence of PE is 1.6%, and more than half of these (0.9%) are fatal. In comparison, the DVT rate among high-risk orthopedic patients is substantially greater. Untreated patients following THR have a DVT rate of 50-60%, with a 20-30% proximal DVT rate. The overall incidence is even greater in patients after total knee replacement (TKR), with a 60-85% DVT rate, although, the proximal DVT rate is less, 9-20%. Patients with hip fractures have a DVT rate of 30-60%, with a proximal DVT rate of up to 36%. In these same series, the risk of fatal PE ranges 0.4-12.9%. Therefore, because VTE disease is often silent, with significant consequences both in morbidity and mortality in untreated DVT and PE, offering those high-risk patients protection in the form of DVT prophylaxis is obligatory. A study reported in the Archives of Internal Medicine in February 2000 involved 2000 patients in 10 hospitals to observe the number that received optimal DVT prophylaxis as defined by the American College of Chest Physicians (ACCP). The number of individuals with THR who received optimal DVT prophylaxis was 84.3%, in persons with TKR, it was 75.9%; and in patients with hip fractures, it was 45.2%. Only 50.4% of high-risk general surgery patients received optimal prophylaxis. Pulmonary embolus is not the only complication of DVT. A patient who has had VTE is at increased risk of developing a condition called postthrombotic syndrome (PTS), a condition characterized by venous stasis ulceration, severe chronic leg pain and intractable lower extremity edema. In a study of 355 post DVT patients, the incidence of PTS was 17.5% after 1 year, 22.8% after 2 years and 28% after 5 years. A recent survey of the American Association of Hip and Knee Surgeons indicated that 100% of their members were providing some method of DVT prophylaxis. In 2003, the Hip and Knee Registry reported in 2003 that 1 or more types of thromboprophylaxis was used in 99% of patients. About 89% of total hip arthroplasty (THA) patients and 91% of total knee arthroplasty (TKA) patients received therapy matching the prophylaxis recommendations of the ACCP.
Certain factors predispose individuals to thromboembolic disease. Recently attempts have been made to quantify the risk levels associated with certain factors. The ACCP Sixth Consensus Conference on Antithrombotic Therapy was published in January 2001. A new conference supplement, the Seventh Consensus Conference, is expected to be published in the fall of 2004.
The risk factor assessment guidelines include the following list of factors that increase the risk of DVT:
These factors include those that diminish venous flow or return, increase viscosity, or alter mobility. Age is one of the most easily definable factors. The risk of DVT increases in exponential fashion with increasing age (see Image 6).
In addition, recognition of certain hypercoagulable states caused by congenital hematologic abnormalities is growing. They include the following:
Patients with a prior history of DVT or PE have demonstrated an incidence of a congenital thrombophilic abnormality as high as 25%. Congenital abnormalities are as follows:
Both Rosendaal and Kearon analyzed the relative contribution of each of these risk factors to the development of DVT. When more than 1 risk factor is present, the risk is cumulative.
By using the risk criteria listed above, orthopedic patients can be categorized into 4 risk groups ranging from low to very high. The risk grouping system by Geerts et al is a helpful guide:
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Screening methods in use for the diagnosis of DVT range in their specificity and selectivity. Studies that report on the incidence of DVT vary considerably, depending on the endpoint of diagnosis used. Radioactive FUT lacks both specificity and sensitivity. Duplex Doppler sonography has poor sensitivity for distal thrombi and is highly dependent on the technician for reproducible results. However, Doppler study is noninvasive and accurately evaluates proximal DVT, which are more dangerous clinically from the standpoint of propagation and PE development. The use of duplex Doppler imaging as a screening test for asymptomatic patients on discharge is unreliable in predicting future DVT (see Image 7). Venography has been used as the criterion standard for DVT diagnosis, and it is accurate in demonstrating both distal and proximal thrombi (see Image 8). The disadvantages of venography are that it is painful and invasive. Disagreement also exists about the clinical significance of the thrombi detected. However, despite these shortcomings, it is still the method of comparison used in many of the clinical studies of the effectiveness of prophylactic regimens. Diagnosing intrapelvic thrombi has been difficult until recently, with the advent of magnetic resonance (MR) venography. This technique has provided physicians the ability to diagnose intrapelvic and proximal DVT in patients in whom venography is not possible or unlikely to be diagnostic. PE is commonly diagnosed on the basis of symptoms of chest pain and dyspnea (shortness of breath). ECG may demonstrate ST-segment changes. The arterial oxygen saturation (PaO2) level may be lowered. All or none of these findings may be present, and the embolization may remain subclinical or silent. PE is most often diagnosed by means of ventilation/perfusion lung scanning, which is reported as having a low, moderate, or high probability of depicting PE (see Image 9). When the results of these studies are equivocal, the use of spiral CT scans may be able to demonstrate intravascular thrombosis (see Image 10). In many institutions, the criterion standard for diagnosing PE is pulmonary angiography (see Images 11-12).
Mechanical methods of DVT prophylaxisIPC devices are designed to decrease venous stasis, improve blood flow velocity, and increase the level of circulating fibrinolysins. IPC devices have the advantage of requiring no monitoring, with no increase in bleeding. Generally, they are well tolerated. These devices come in a wide variety and can be applied to the foot, calf, or thigh. No comprehensive prospective study has been done to evaluate the relative efficacy of these devices. Patient compliance is an issue with IPC devices, and the efficacy is dependent on the time of use. Evidence from clinical trials has also shown that while the rate of distal thrombi is reduced significantly, proximal thrombi are not. This finding may lead to a false sense of security because the total numbers of DVT may be similar to the numbers observed with pharmacologic prophylaxis and because the proportion of the relatively more dangerous proximal clots is increased (see Table 2). Shorter lengths of hospital stays make the use of mechanical methods alone ineffective in preventing DVT in the critical weeks after joint replacement. Table 2. Results of IPC versus warfarin
Pharmacologic methodsMany pharmacologic agents are currently available to prevent thrombosis. Agents that retard or inhibit the process belong under the general heading of anticoagulants. Agents that prevent the growth or formation of thrombi are properly termed antithrombotics and include anticoagulants and antiplatelet drugs, whereas thrombolytic drugs lyse existing thrombi. Platelet-active drugs Platelet-active drugs such as aspirin or cyclooxygenase-1 (COX-1) inhibitors have been used to prevent thrombosis. Aspirin is effective as a platelet inhibitor at very low doses (50-100 mg/d). This dose is significantly less than that necessary to produce an anti-inflammatory effect. A meta-analysis of the effect of aspirin following THR completed in 1994 had equivocal results. A large study performed in Europe, the Pulmonary Embolism Prevention (PEP) study, included 13,356 patients with hip fractures and 4088 patients with THR. The patients were given a 160-mg/d dose compared with placebo and evaluated at day 35. Approximately 40% of the patients also were given LDH or LMWH. With this regimen, the overall DVT rate was decreased 30% compared with placebo, and the overall PE rate was decreased by 40%. In a concomitant study of 4088 patients with THRs, a 25% reduction of DVT was observed in comparison with the placebo control. No decrease was noted in the rate of PE. This trial did not show a clear benefit of using aspirin as the primary method of venous prophylaxis in either patients undergoing total hip or total knee surgery. The Seventh ACCP Conference does not recommend the use of aspirin alone as a prophylactic agent. Coumarins Coumarins are a class of oral anticoagulant drugs, which act as antagonists to vitamin K. The mechanism of action is to interfere with the interaction between vitamin K and coagulation factors II, VII, IX, and X. Vitamin K acts as a cofactor at these levels. Coumarins produce their anticoagulant effect by inhibiting the carboxylation necessary for biologic activity. Warfarin is a mixture of 2 isomers; the R and S forms in roughly equal proportions. Warfarin is absorbed rapidly from the GI tract and bound to plasma proteins. Although it has high bioavailability, warfarin requires 36-72 hours to reach a stable loading dose. The dose response in patients taking warfarin is variable, and it is influenced by various genetic and environmental factors. Numerous drug interactions and disease states may affect its pharmacokinetics. The effectiveness of coumadin anticoagulation is measured by determining the prothrombin or protime against a standard control. The use of international normalized ratio (INR) has supplanted the protime for hospital use. INR uses a standardized protime, which allows for comparisons between hospitals and laboratories. For DVT prophylaxis, the optimal INR level is between 2.0 and 3.0, with a target of 2.5. When used for DVT prophylaxis after THR, warfarin reduces total DVT by 60% and proximal DVT by 70%. Disadvantages of warfarin use include its long onset of action, the necessity to monitor INR values frequently to obtain stable dosage, the long half-life that may require vitamin K reversal in incidents of hemorrhage, frequent drug and dietary interaction, and variable patient response. Hemorrhagic complications are reported in up to 3-5% of patients on warfarin prophylaxis. If adjusted-dose warfarin is to be used, it is started the night prior to surgery and continued postoperatively during the discharge period. INR target levels usually are not reached until the third postoperative day. Heparins Standard unfractionated heparin (UHF) also is recognized as an acceptable anticoagulant modality. UHF has been used for this purpose in various forms since its discovery by McLean in 1916. UHF acts in conjunction with a circulating plasma cofactor, ATIII and, in its presence, catalyzes the inactivation of factors IIa, Xa, IXa, and XIIa. By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of factor V and factor VIII. Of these, factors IIa and Xa are most sensitive. Therefore, heparin has both anticoagulant and antithrombotic properties. Heparin is a heterogeneous mixture of molecules that contain a range of molecular weights of 3,000-30,000, with an average of approximately 15,000. Only one third of the heparin molecules have an active binding site for ATIII, and this fraction is responsible for most of the anticoagulant activity. Heparin is effective when given by intravenous (IV) or subcutaneous (SC) administration but is inactivated in the GI tract. Heparin has a rapid onset of action, its half-life is brief in comparison to warfarin, and it binds to platelets, endothelial cells and macrophages in vivo. Therapeutic levels of heparin are measured by the activated partial thromboplastin time (aPTT). Because of the rapid clearance of heparin from the bloodstream, therapeutic levels (aPTT of 1.2-1.5 times control) are more likely achieved with continuous IV infusion. Postoperative DVT prophylaxis with UHF usually is achieved by administering a bolus of 5000 U every 8 hours. This LDH regimen results in a 60-70% reduction of DVT and PE in low- or moderate-risk patients. However, this method is not as effective in patients who are at high risk for development of DVT or PE. In these patients, adjusted-dose heparin with aPTT monitoring is preferred to maintain the desired anticoagulant level. Studies have demonstrated a high hemorrhagic complication rate of 8-15% when this method is used for postoperative DVT prophylaxis. Heparin overdosage is reversible with protamine sulfate, which itself is an anticoagulant. Each milligram of protamine sulfate can neutralize approximately 100 U of heparin activity. It must be administered very slowly by IV infusion over a 10-minute period in doses not to exceed 50 mg. Because heparin is cleared rapidly from the circulation, the amount of protamine required decreases rapidly as the time from initial heparin administration increases. The final dosage required is titrated according to coagulation studies. Disadvantages of UFH therapy include variable pharmacokinetics, the requirement for aPTT monitoring for adjusted-dose regimens, short half-life and low bioavailability, and lack of oral dosage form (although an oral form is currently in clinical trials). In addition, a small percentage of patients (2-4%) are susceptible to the development of heparin-induced thrombocytopenia (HIT), which is an antibody-mediated adverse reaction that can cause venous and arterial thrombosis. HIT is heralded by an otherwise unexpected fall in platelet count of greater than 50% from prior levels. HIT can result in disseminated intravascular coagulation and gangrene in severe cases. Treatment with danaparoid sodium or recombinant hirudin, such as lepirudin, may be effective in life-threatening cases. Low-molecular-weight heparins LMWHs are manufactured when standard heparin is treated by a variety of enzymatic or chemical methods to select those lower molecular weight moieties that contain the active ATIII binding site. The average molecular weight of fractionated heparin is 4500 in comparison to the usual 15,000. The molecular weight threshold under which anti–factor Xa activity is maximized is 5400 Da. The polysaccharide side chain of the heparin molecule is decreased from 18 U to approximately 13 U. As the length of the side chain is decreased, the ability of the molecule to prolong the aPTT is lost, but the ability to complex with ATIII is retained. LMWHs do not require monitoring of either aPTT or INR (see Image 13). The pharmacologic effect of this transformation is to make the LMWH more bioavailable (approximately 90%, compared with 29% for UFH) and to lengthen its half-life to 4 hours from 1 hour for UFH. LMWH also increases the activity ratio of anti-Xa to anti-IIa, resulting in increased antithrombotic activity. In experimental models and animal studies, LMWH produces less microvascular bleeding than UFH, but this finding has not been duplicated in human trials. Compared to placebo, LMWHs produced a 70-80% risk reduction for DVT in numerous studies without an increase in major bleeding in high-risk orthopedic patients. Meta-analysis comparison with a variety of other methods of DVT prophylaxis, including low-dose UFH, adjusted-dose heparin, and warfarin, have demonstrated improvement in DVT prophylaxis without increase in hemorrhagic complications (see Tables 3-4). Table 3. Incidence of DVT by prophylactic medication
Table 4. LMWH versus warfarin after THR: meta-analysis of results from 5 studies
LMWH preparations include the following:
Several attempts have been made to quantify the risk factors associated with VTE disease. The use of a checklist to stratify patients and assign them to categories of relative propensity for DVT development is helpful in deciding on an appropriate treatment regimen. A list can be constructed using the ACCP risk categories (see ACCP risk factor assessment guidelines). These figures include a list of the pertinent factors, which are arbitrarily assigned a score of 1. An individual aged 61-70 years is assigned 2 units; a person older than 70 years is assigned a score of 3, as is an individual with a prior history of thrombosis, inherited thrombophilia, antiphospholipid antibodies, or lupus anticoagulant. The total score is then added.
Suggested regimens for each risk category are as follows:
The ACCP provides recommendations for specific treatment of patients following THRs as follows:
The following are ACCP recommendations for specific treatment of patients following TKRs:
ACCP recommendations for patients with hip fractures are as follows:
Studies have demonstrated that patients undergoing THR remain at increased risk for the development of DVT for up to 3 months postoperatively. Two definite peaks have been demonstrated in DVT initiation, POD 4 and POD 13-14 (see Image 14). In patients with additional risk factors, the potential for DVT may last longer. Several studies have demonstrated that the incidence of DVT at postoperative day 21 in patients with no postoperative prophylaxis can be as high as 39%, with a symptomatic PE rate of 1.7%. Extended prophylaxis with LMWH or warfarin lowers this rate considerably (see Table 5). Therefore, LMWH or other prophylaxis should be continued after TKR for 10 days and THR patients for 3 weeks. In high-risk patients, prophylaxis should last 30-40 days or longer postoperatively. This therapy can reduce total and proximal DVT by at lease 50% without increasing major bleeding events. Patients with a history of prior DVT or PE and those who have inherited thrombophilia may require even longer treatment. Table 5. Extended DVT Prophylaxis After THR*
Long-term anticoagulant prophylaxis or treatment of established DVT usually requires continued treatment after hospitalization. At the time of this writing, there are no FDA-approved pharmacologic agents that can be given orally without laboratory monitoring. Outpatient therapy with LMWHs is both safe and effective. However, a mechanism should be available for either self-administration of SC medication or to teach caregivers to administer the medication. Visiting nursing services may also provide this service. Unfortunately, many insurance companies do not cover out-of-hospital expenses. For this reason, a common practice is to overlap the initiation of oral warfarin therapy with LMWH treatment while the patient is still hospitalized. When the INR has been at a therapeutic level for 48 hours, LMWH can be discontinued. Contraindications to anticoagulant therapy Complications of anticoagulant treatment include major and minor bleeding, hematoma formation, compartment syndrome, and HIT. Major bleeding is defined as hemorrhage that alters the clinical course of the patient's treatment or changes the clinical outcome. Major bleeding may prolong the hospital stay, necessitate a return to the operating room, or result in unexpected transfusion. DVT prophylaxis should be delayed or terminated in these cases. Rehabilitation or mobilization may also be delayed. Absolute contraindications to anticoagulant therapy include active hemorrhage or an unstable condition of a patient with multiple traumas. Patients with HIT should not be given standard anticoagulants; instead, they should be treated with one of the newer methods specifically approved for such use. Warfarin should not be used in patients who are pregnant. Patients who have sustained severe head trauma or acute SCI should not undergo anticoagulation. Indwelling spinal catheters should be withdrawn, with a 2-hour delay before initiating anticoagulation. Relative contraindication to anticoagulation includes patients with previous history of cerebral or GI hemorrhage. Patients with history of thrombocytopenia or coagulopathy may have circulating heparin antibodies. Patients with active intracranial lesions or neoplasm may be at increased risk for bleeding on anticoagulant therapy. Proliferative retinopathy also may put patients at increased risk for intraocular bleeding. While it is beyond the scope of this discussion, the use of inferior vena caval filters are useful in patients who have a contraindication to the use of anticoagulants or in those in whom treatment has not been successful. Filter protection from PE was significant in short-term studies, but it became less effective after 1-2 years (Decousus, 1998). Bates and Ginsberg have reviewed the current treatment of established DVT.
An ideal anticoagulant should be easy to administer (preferably oral), should be effective and safe with minimum possible complications or adverse effects, have rapid onset, have a therapeutic half-life, and require minimal or no monitoring. The action of the anticoagulant should be predictable with few drug or dietary interactions, and it should be reversible. The drug should also be inexpensive. These criteria are often difficult to achieve. Several anticoagulant agents exist today, and each of them incorporates some of these characteristics, but no one combines all these attributes. Current research in anticoagulants involves investigations into drugs that act on various phases of the coagulation cascade. For convenience, the authors can arbitrarily divide the process into 3 phases: the initiation phase, the propagation phase, and the thrombin activity phase. Drugs under investigation that act in the initiation phase include tissue factor pathway inhibitors (TFPIs) and nematode anticoagulant peptide (NAPc2). These drugs act through inhibition of the factor VIIa/tissue factor complex. A new drug fondaparinux sodium (Artixtra; Sanofi-Synthelabo) affects the propagation phase and is related to the LMWHs. It is a synthetic pentasaccharide, an ultra-low-molecular-weight heparin, made completely under laboratory conditions. In 2002, the FDA approved this medication for the prevention of DVT after major orthopedic surgery. The drug acts as a selective inhibitor of factor Xa, it has no anti-IIa activity, and it requires no monitoring because it has no effect on either aPTT or prothrombin time (PT). The results, as reported in the New England Journal of Medicine in March 2001 indicate that the drug (2.5 mg SC once daily) is equivalent to or superior to LMWH. Turpie found that major bleeding complications occurred somewhat more frequently in the fondaparinux group (2.7%) than in the enoxaparin group (1.7%) but this may have been due to the timing of the first postoperative injection (6 h). Fondaparinux does not induce antibody-mediated thrombocytopenia. Drugs that act on the third stage of the coagulation cascade, the thrombin activity phase, include the direct thrombin inhibitors. These drugs specifically inactivate thrombin and are independent of antithrombin ATIII. Included in this group are the hirudins and its derivatives made by recombinant DNA techniques. Originally, hirudin was isolated from leech salivary gland tissue. The new drugs include bivalirudin (Angiomax) and lepirudin. A randomized, multicenter, double-blind study of hirudin versus heparin in patients with THRs demonstrated DVT and proximal DVT rates were decreased substantially in the hirudin group. Another class of drugs acting at the third level of the coagulation cascade includes the noncovalent inhibitor argatroban, which is a carboxylic acid derivative that has been approved for use in the treatment of HIT. A recent and promising new direct thrombin inhibitor is an oral prodrug of melagatran named ximelagatran (Exanta; AstraZeneca). It is rapidly absorbed through the GI tract, where it is converted to its active form, melagatran. It does not require monitoring; it has a rapid onset of action, a predictable dose-response and a therapeutic half-life. Also, like the other direct thrombin inhibitors, it does not affect the aPTT or PT. Phase 3 human clinical trials have been completed, and the results reported by Francis et al in the New England Journal of Medicine. Ximelagatran and warfarin did not differ significantly with respect to the incidence of major or minor bleeding, and ximelagatran was significantly more effective in preventing DVT when compared to warfarin after TKR. In the US, 4 studies have shown that postoperatively initiated ximelagatran (24 mg twice daily) had efficacy similar to that of enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those of comparator anticoagulants. Some patients experienced transient elevations of liver enzyme levels, which returned to normal after cessation of treatment. Other studies have also shown that ximelagatran is effective in preventing thrombosis associated with atrial fibrillation and in the treatment of established DVT. Conclusion Major surgical and high-risk orthopedic procedures place patients at risk for DVT and VTE, including PE. Complications of DVT include postphlebitic syndrome or death from PE. Therefore, prophylaxis with anticoagulant medications, as well as mechanical devices, is essential. The most effective treatment protocol for a patient must be determined on a case-by-case basis and account for the risk-benefit ratio in each situation. A risk stratification protocol, such as that developed by the ACCP, is recommended to determine the appropriate level and method of treatment. For excellent patient education resources, visit eMedicine's Circulatory Problems Center and Lung and Airway Center. Also, see eMedicine's patient education articles Blood Clot in the Legs and Pulmonary Embolism.
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