Venous thromboembolism (VTE) is manifested clinically by deep venous thrombosis (DVT) and pulmonary embolism (PE). DVT, usually of the lower extremity, nearly always precedes PE. The risk of VTE increases greatly after age 50. In addition to age, major acquired risk factors are trauma, immobilization, and surgery, along with others (Table 1). The anti-estrogen tamoxifen also increases the risk of VTE. Individuals with inherited conditions that increase risk (thrombophilia) usually present before age 40, although it is not unusual to see the first episode of VTE in a patient with factor V Leiden appear after total hip replacement at age 65. The disease most often occurs in hospitalized patients, particularly those with cancer or following surgical procedures, but also occurs sporadically in the community. In both settings, multiple risk factors are usually present.
In a geriatric population, diagnosis of VTE presents particular problems because PE can mimic a lingering pneumonia or congestive heart failure. Diagnosis requires a high index of suspicion in anyone with unexplained dyspnea, which can indicate PE, or leg swelling or pain, which can indicate DVT. It is important to remember that 97% of patients with PE will have one or more symptoms or signs: dyspnea, pleuritic pain and a respiratory rate greater than 20 breaths per minute.
Spiral chest CT scanning with contrast has become increasingly accepted as the initial test of choice for diagnosing PE. The test is highly specific (>90%) but has an overall sensitivity of about 80% because it misses small PE in subsegmental or smaller pulmonary arteries. For acceptable sensitivity, spiral chest CT should be combined with a leg study, such as duplex ultrasound or a venous-phase leg CT from the same contrast injection used for the spiral chest CT. When both the spiral chest CT and a leg study are used, VTE is detected with more than 90% sensitivity. When results of both tests are negative, it is acceptable to withhold anticoagulation unless the clinical suspicion of VTE remains high. If it does, additional tests, such as contrast venography, V/Q lung scans or pulmonary angiography, should be done, depending on the circumstances. In outpatients with low or moderate suspicion of VTE, a negative or normal serum D-dimer measurement is sufficient to withhold anticoagulation. Measurement of D-dimer is much less useful in the hospital because most inpatients have elevated D-dimer levels.
Effective anticoagulation and early mobilization are important elements of VTE treatment. Low-molecular-weight heparin (LMWH) is a good initial therapy because it has a predictable anticoagulant effect and allows early hospital discharge or even home therapy in selected patients. LMWH products are dosed on body weight, and no change in dose is necessary in the elderly. It is important to start warfarin on day one and overlap warfarin and the heparin product for at least 5 days, also confirming that the international normalized ratio (INR) is in the target range of 2.0 to 3.0 before heparin is stopped. Shortening the course of unfractionated heparin or LMWH by starting warfarin on day one of VTE treatment is useful to minimize the risk of heparin-induced thrombocytopenia (HIT). Whereas 5 to 10 mg of warfarin is often a suitable starting daily dose in younger patients, patients over age 65 and those weighing less than 40 kg should usually be started on a dose of 2 to 3 mg. These patients also can often be maintained on lower doses. The duration of anticoagulation should be tailored according to both recurrence risk and bleeding risk (Table 2), as well as the patient's wishes. Maintaining the INR in the target range of 2.0 to 3.0 minimizes recurrence risk without significantly increasing bleeding risks and is preferred over an INR range of 1.5 to 2.0 for long-term treatment of VTE. A frequently overlooked therapeutic intervention in patients with DVT is the use of elastic support hose. A 2004 study in Annals of Internal Medicine by Prandoni and colleagues showed that wearing a well-fitted pair of below-knee elastic support hose (30 to 40 mm Hg at the ankle) for 2 years reduced the long-term rate of post-phlebitic thrombotic syndrome by 50%.
Treatment in special populations
HIT occurs when antibodies to a heparin-platelet factor 4 complex induce platelet activation and consumption. The extreme example of the clinical consequence of HIT is arterial or venous thrombosis (HITTS). Stroke, myocardial infarction, VTE and limb or bowel ischemia can occur. HIT should be suspected any time the platelet count falls below 100,000 cells/µL or otherwise falls by 50% compared with baseline. Fortunately, HIT is rare, occurring in less than 1% of patients who receive heparin. Orthopedic surgery patients, who receive heparin for longer than 7 days, and cardiac surgery patients, who receive heparin in interrupted intervals, are at highest risk. The syndrome usually appears between the fifth and tenth day of therapy, although it can happen earlier in patients who have had recent exposure to heparin. It can also appear later or even after therapy has stopped, particularly in patients receiving LMWH. When HIT is suspected, heparin should be stopped and the patient should be given a parenteral direct thrombin inhibitor, either argatroban or lepirudin. Warfarin should not be used at this point; if it has already been started, it should be stopped and its effect reversed with vitamin K. This is because warfarin can block the fibrinolytic process and cause what is termed “warfarin necrosis.” HIT is divided into two types: one that is reversible, and one that is rare with fatal implications. Consultation with a hematologist is advised in some cases of HIT.
Antiphospholipid antibody syndrome (APAS) occurs spontaneously and in association with several medical conditions, notably connective tissue diseases. The phenomenon was first recognized as the lupus anticoagulant syndrome, which is named for its association with systemic lupus erythematosus (SLE), although a circulating anticoagulant of this type can occur in the absence of SLE. The syndrome predisposes to both arterial and venous thrombosis. When VTE occurs in conjunction with APAS, treatment is similar to that given to other patients with VTE. Some authorities also recommend adding 81 mg of aspirin daily because of the increased risk of arterial thrombosis associated with APAS.
In patients with renal failure, there are special considerations regarding anticoagulants. All the LMWHs and fondaparinux are cleared renally, and these drugs can accumulate in plasma in patients with creatinine clearances below 30 mL/min. This consideration is particularly important in the frail elderly who may have decreased renal function despite a serum creatinine at the upper end of the normal range. Recently, guidelines have been issued to clarify the use of enoxaparin in patients with significant renal insufficiency (creatinine >1.8) as recommended in the package insert and Physicians' Desk Reference.
Patients with cancer who develop VTE are at higher risk of both recurrence and death than other patients with VTE. Because of improved treatment and longer survival, patients with cancer account for an increasing proportion of those with VTE. VTE can occur before cancer is evident, at the time of the cancer diagnosis and at any point in the clinical course of patients with known cancer. VTE is particularly likely to occur during intensive chemotherapy and as a complication of cancer surgery. For years, clinicians have been aware of so-called “warfarin failure”-the tendency to develop recurrent VTE despite an INR between 2.0 and 3.0-in patients with VTE and cancer. Recent clinical trials have shown that long-term LMWH in a treatment dose reduces the recurrence rate of VTE in cancer patients by 50% compared with warfarin (INR 2 to 3). The new therapeutic recommendation for treatment of patients with cancer and VTE is LMWH in a treatment dose for 3 to 6 months. At that point, the clinician has the option of continuing the LMWH or switching to warfarin (INR 2 to 3).
Fondaparinux is a small (molecular weight 1726 daltons), synthetic indirect factor Xa inhibitor. It is a parenteral agent given subcutaneously once daily. It acts by binding to antithrombin and facilitating antithrombin's inhibition of factor Xa. In this regard it is similar to LMWH, but its small size and synthetic nature make it a different class of drug. Fondaparinux does not require monitoring or dose adjustment in patients who have normal to moderately impaired renal function. The incidence of HIT appears to be negligible with fondaparinux, and the drug has actually been used to treat patients with HIT. Fondaparinux currently has indications for prevention and treatment of VTE. It has been shown to be particularly effective in preventing VTE after hip fracture surgery when given for 1 month following surgery.
Direct thrombin inhibitors bind directly to the active site of thrombin without need of the cofactor, antithrombin. The first of these experimental agents, ximelagatran, has been withdrawn from the market because of liver toxicity. However, several other direct thrombin inhibitors are currently under study. Ximelagatran is a pro-drug given twice daily in a fixed dose and does not require anticoagulation monitoring or dose adjustment. The drug is rapidly hydrolyzed to the active agent, melagatran. Melagatran is cleared renally and dose adjustments are probably necessary in patients with severe renal impairment (creatinine clearance <30 mL/min). The drug's onset of action occurs within 1 hour, and consequently it would have theoretically been useful for both acute and chronic treatment of thrombotic diseases.
Prevention of VTE is especially important in older patients who are undergoing surgery or are hospitalized for a medical condition. Surgical patients at highest risk include those undergoing orthopedic procedures on the lower extremity and those undergoing cancer surgery. Medical patients at high risk include those with heart or respiratory failure, stroke, cancer and serious infections such as pneumonia. Table 3 gives recommended prophylactic measures in patients according to risk group.
The syndrome of “economy-class VTE” seems to be precipitated by immobilization and dehydration associated with long airplane flights. Risk appears to increase greatly when a flight exceeds 5 hours. On long flights, older travelers should get out of their seats and walk around the cabin every 2 hours. Wearing a pair of surgical support hose during the flight is also a good idea. Travelers with a history of VTE or who are otherwise at increased risk should probably receive a subcutaneous injection of LMWH, fondaparinux, or unfractionated heparin before boarding the flight. The prophylactic benefit of aspirin in this setting is uncertain but is likely to be small.