Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), affects about 1 in 1000 persons annually. The incidence and case-fatality of venous and arterial thromboembolic events increase with age. The increased risk of VTE in elderly patients reflects the increased prevalence of risk factors (temporary and permanent), prothrombotic changes in coagulation with advanced age, and an independent contribution of advancing age.

The diagnosis of VTE is more challenging in the elderly patient, as clinical presentations are more often atypical than in younger patients and the diagnostic properties of some tests appear to be influenced by advancing age. However, the general approach to diagnosis of VTE in the elderly is much the same as in younger patients.

While anticoagulant therapies have comparable relative risk reductions for prevention of VTE in older compared to younger patients, elderly patients are at increased risk of major bleeding and particularly intracranial bleeding. Therefore, decisions regarding optimal duration of anticoagulant therapy for VTE are influenced by the patient’s age.

In this chapter, we review the epidemiology, pathophysiology, natural history, diagnosis, and treatment of VTE in the elderly patient.

Incidence of VTE

The incidence of VTE increases exponentially with advancing age (i.e., approximately twofold increase with each decade) rising from an annual incidence of 0.03% at age 40 years, to 0.09% at 60 years, and 0.26% at age 80 years.

Risk Factors

Most patients with VTE have one or more clinical risk factors for venous thrombosis. The most common risk factors in hospitalized elderly patients are recent surgery, previous VTE, trauma, and immobility, as well as serious illness, including malignancy, chronic heart failure, stroke, chronic lung disease, acute infections, and inflammatory bowel disease. A particularly important major risk factor for VTE in elderly patients is major orthopedic surgery, both elective and after hip fracture, where fatal PE is a leading cause of in-hospital death. Common risk factors in outpatients include hospital admission within the past 3 months, malignancy, previous VTE, cancer chemotherapy, estrogen therapy, presence of an antiphospholipid antibody, and familial thrombophilia. Less common risk factors are paroxysmal nocturnal hemoglobinuria, nephrotic syndrome, and polycythemia vera. A recent study of elderly patients has reported frailty to be a risk factor for VTE.

Age is thought to have at least an additive influence on the risk of VTE when combined with other risk factors for VTE and the prevalence of many risk factors is greater in the elderly. Consequently, the risk of VTE in high-risk situations, such as following surgery, is greater in older than younger persons.

The risk of thrombosis is about 50-fold higher in persons with a previous VTE than in the general population, and recurrent thrombosis accounts for about one quarter of all acute episodes of VTE. When anticoagulant therapy is stopped after 3 or more months of treatment, the subsequent risk of recurrent VTE in the first year varies from about 2% in patients who had VTE provoked by a transient risk factor, to about 10% in those with an unprovoked VTE or a continuing risk factor for thrombosis. There is some evidence that older age may be associated with a higher risk of recurrent VTE after anticoagulants are stopped, but this is uncertain and poorly quantified.

Venous stasis and damage to the vessel wall predispose to thrombosis. Venous stasis is produced by immobility, obstruction or dilatation of veins, increased venous pressure, and increased blood viscosity. The critical role of stasis in the pathogenesis of venous thrombosis is illustrated by the observation that thrombosis occurs with equal frequency in the two legs of paraplegic patients but occurs with much greater frequency in the paralyzed limb than in the nonparalyzed limb in stroke patients.

Venous thrombi usually arise at sites of vessel damage, or in the large venous sinuses of the calves, or the valve cusp pockets of the deep veins of the calves, and are composed predominantly of fibrin and red blood cells. Thrombosis occurs when blood coagulation overwhelms the natural anticoagulant and fibrinolytic systems. Coagulation is usually triggered by exposure of blood to tissue factor on the surface of activated monocytes that are attracted to sites of tissue damage or vascular trauma. Clinical risk factors that activate blood coagulation include extensive surgery, trauma, burns, malignant disease, myocardial infarction, cancer chemotherapy, and local hypoxia produced by venous stasis.

Tissue damage also results in impaired fibrinolysis, which occurs through the release of inflammatory cytokines in response to the damage. These cytokines induce endothelial cell synthesis of plasminogen activator inhibitor-1 (PAI-1) and reduce the protective effect of the vascular endothelium by downregulating the endothelial-bound anticoagulant thrombomodulin.

Stasis resulting from venous dilatation occurs in elderly patients, in patients with varicose veins, and in women who are pregnant or using supplemental estrogen. Venous obstruction contributes to the risk of venous thrombosis in patients with pelvic tumors. Increased blood viscosity, which also causes stasis, may explain the risk of thrombosis in patients with polycythemia vera, hypergammaglobulinemia, or chronic inflammatory disorders. Direct venous damage may lead to venous thrombosis in patients undergoing hip surgery, knee surgery, or varicose vein stripping and in patients with severe burns or trauma to the lower extremities.

Blood coagulation is modulated by circulating, or by endothelial cell-bound, inhibitors of thrombosis. The most important circulating inhibitors of coagulation are antithrombin, protein C, and protein S. An inherited deficiency of one of these three proteins is found in about 20% of patients who have a family history of VTE and whose first episode of VTE occurs before 41 years of age. Some types of congenital dysfibrinogenemias can also predispose patients to thrombosis, as can a congenital deficiency of plasminogen. However, these are rare causes of venous thrombosis in the elderly presenting with first VTE episode. An inherited thrombophilic defect known as activated protein C (APC) resistance, or factor V Leiden, is the most common cause of inherited thrombophilia, occurring in about 5% of whites who do not have a family history of VTE and in about 20% of patients with a first episode of VTE. One case–control study reported that factor V Leiden was not a risk factor for VTE in patients older than 70 years but associated with threefold increase in younger patients. The second most common thrombophilic defect is a mutation (G20210A) in the 3′-untranslated region of the prothrombin gene that results in about a 25% increase in prothrombin levels. This mutation is found in about 2% of whites with no family history of VTE and in about 5% of patients with a first episode of VTE. Elevated levels of clotting factors VIII and XI also predispose patients to thrombosis. Randomized trials have shown that the administration of estrogens in the doses used for postmenopausal hormone replacement therapy increase the risk of a first or recurrent thromboembolism about threefold, with highest risk being within the first 6 months of starting therapy.

Most venous thrombi produce no symptoms and are confined to the intramuscular and deep veins of the calf. Many calf vein thrombi undergo spontaneous lysis, but some extend into the popliteal and more proximal veins. Complete lysis of proximal vein thrombosis is less common. Most symptomatic pulmonary emboli and virtually all fatal emboli arise from thrombi in the proximal veins of the legs.

Although venous thrombosis can occur in any vein in the body, it usually involves superficial or deep veins of the legs. Thrombosis in a superficial vein of the leg is generally benign and self-limiting but can be serious if it extends from the long saphenous vein into the common femoral vein. Superficial thrombophlebitis is easily recognized by the presence of a tender vein surrounded by an area of erythema, heat, and edema. A thrombus can often be palpated in the affected vein. Thrombosis involving the deep veins of the leg maybe confined to calf veins or may extend into the popliteal or more proximal veins. Thrombi confined to calf veins are usually small, often asymptomatic, and are rarely associated with PE. About 20% of calf vein thrombi, however, extend into the popliteal vein and beyond, where they can cause serious complications. In most cases, extension of calf vein thrombosis occurs within a week. About 50% of patients with symptomatic proximal vein thrombosis also have clinically silent PE, and about 70% of patients with symptomatic PE have DVT, which is usually clinically silent. Untreated or inadequately treated VTE is associated with a high rate of complications, with about 50% of untreated proximal vein thrombi undergoing symptomatic extension or embolization (see “Treatment of Venous Thromboembolism”).

Acute Consequences of Venous Thromboembolism

In general, one-third to one-half of first episodes of VTE present as PE, the remainder presenting as DVT. It is estimated that about 10% of symptomatic PE are rapidly fatal and that about 5% of patients that are treated for PE die of a recurrence (mostly within the first 3 months). There is evidence that in the elderly, a larger proportion of episodes of VTE presents as PE and, when PE occurs, it is more likely to be fatal (i.e., four times higher than in patients 45 years of age or younger). In patients who are being closely monitored (e.g., in clinical trials), about 5% of recurrent episodes of VTE that occur after anticoagulants have been stopped are fatal. If the initial episode of VTE is a PE, recurrent episodes are also more likely to be a PE than DVT and, therefore, are more likely to be fatal. As with a first episode of VTE, the case-fatality of recurrent episodes of thrombosis may be higher in the elderly although this is uncertain.

Chronic Complications of Venous Thromboembolism

While PE is the most serious and most feared complication of venous thrombosis, important chronic conditions may also occur after acute VTE. Postthrombotic syndrome is the most frequent chronic complication of DVT of the leg. Characterized by pain and swelling, it is responsible for considerable personal disability, reduced quality of life, and substantial health care costs (estimated at $250 million per year in North America). The postthrombotic syndrome occurs as a long-term complication in about 25% (and is severe in about 10%) of patients with symptomatic proximal vein thrombosis in the 8 years after the acute event, with most cases developing within 2 years. The postthrombotic syndrome typically presents as chronic leg pain and swelling, which is worse at the end of the day. Some patients also have stasis pigmentation, induration, and skin ulceration. In a minority of patients, there is venous claudication on walking, caused by persistent obstruction in the iliac veins. Chronic pulmonary hypertension is a more serious complication that occurs in about 4% of patients within 2 years of treated PE.

Deep Vein Thrombosis (Tables 105-1 and 105-2)

Clinical Features

The clinical features of DVT include localized swelling, redness, tenderness, and distal edema. As these symptoms are nonspecific, the diagnosis should always be confirmed by objective investigations. However, clinical assessment does allow division of patients into low, moderate, and high probabilities of DVT, corresponding to prevalence of 15%, 25%, and 60%, respectively. Clinical prediction rules, such as the Well’s Score, are based on four factors; (1) the presence or absence of risk factors (e.g., recent immobilization, hospitalization within the past month, or malignancy), (2) symptoms and signs at presentation are considered typical or atypical, and their severity, (3) severity of symptoms and signs, and (4) whether there is an alternative explanation for the symptoms and signs considered at least as likely as DVT (Table 105-1). The conditions that are most likely to simulate DVT are ruptured Baker cyst, cellulitis, muscle tear, muscle cramp, muscle hematoma, external venous compression, superficial thrombophlebitis, and the postthrombotic syndrome. The prevalence of VTE is higher in the elderly who are investigated, compared to younger patients.

Diagnostic Testing

Four objective tests—venography, impedance plethysmography, and venous ultrasonography, and D-dimer testing—have been rigorously evaluated for the diagnosis of DVT. Impedence plethysmography is now used infrequently, and will not be considered in the following review. Magnetic resonance venography and computed tomography (CT) venography appear to be promising new modalities but are less well evaluated.

Venography

Venography provides the reference standard for diagnosis of DVT. It involves the injection of a radiocontrast agent into a distal vein. Venography detects both proximal vein thrombosis and calf vein thrombosis. However, it is technically difficult, expensive, requires injection of contrast dye and can be painful. Since contrast dye can cause allergic reactions or exacerbate renal impairment, venography is usually reserved to resolve discrepancies between findings on venous ultrasonography and clinical assessment of probability of DVT, or when venous ultrasonography is nondiagnostic (often in patients with previous DVT). The increased prevalence of renal impairment makes venography an even less attractive investigation option in the elderly.

Venous Ultrasonography

Venous ultrasonography is the noninvasive imaging method of choice for diagnosing DVT. It is not painful and it is easier to perform than venography. The common femoral vein, femoral vein, popliteal vein, and calf vein trifurcation (i.e., very proximal deep calf veins) are imaged in real time and compressed with the transducer probe. Inability to fully compress or obliterate the vein is diagnostic of DVT. Duplex ultrasonography, which combines real-time imaging with pulsed Doppler and color-coded Doppler technology, facilitates imaging of the deep veins of the calf.

Venous ultrasonography is highly accurate for the detection of proximal vein thrombosis in symptomatic patients, with reported sensitivity and specificity approaching 95%. The sensitivity for symptomatic calf vein thrombosis is considerably lower and appears to be operator dependent. For this reason, many centers do not examine the deep veins of the calf with ultrasonography. Instead, if the initial test excludes proximal DVT, anticoagulants are withheld and the test is repeated in 7 days to exclude progression of a calf vein thrombosis not identified at the initial presentation. If the test remains negative after 7 days, the risk that thrombus is present and will subsequently extend to the proximal veins is negligible, and it is safe to continue withholding treatment.

While ultrasonography is an accurate test, if the results are inconsistent with the pretest probability, further investigations maybe warranted. For example, if the pretest clinical suspicion for DVT is low and the ultrasound shows a localized abnormality (i.e., less convincing findings), or if clinical suspicion is high and the ultrasound is normal, venography should be considered. In about one quarter of such cases, the results of venography differ from those of the ultrasound. Because the prevalence of DVT is only about 2% (most of which is distal), a follow-up test is not necessary when the clinical suspicion of thrombosis is low and the result of an initial proximal venous ultrasound is normal.

D-dimer Blood Testing

D-dimer is formed when cross-linked fibrin in thrombi is broken down by plasmin; thus, elevated levels of D-dimer can be used to detect DVT and PE. A variety of D-dimer assays are available, and they vary markedly in their accuracy as diagnostic tests for VTE.