ACP medicine, 3rd Edition

Cardiovascular Medicine

Cardiac Tumors

See Chapter XIII

Editors: Dale, David C.; Federman, Daniel D.

Title: ACP Medicine, 2007 Edition

Copyright ©2007 WebMD Inc. (Professional Publishing)

> Table of Contents > 1 - Cardiovascular Medicine > XVIII - Venous Thromboembolism

 Added 2007.01.10

XVIII

Venous Thromboembolism

Clive Kearon MB, PHD1

Jack Hirsh MD, FACP2

1Professor of Medicine, McMaster University, and Head of the Thromboembolism Service, Henderson General Hospital, McMaster University Clinic

2Professor Emeritus, McMaster University, and Director, Hamilton Civic Hospitals Research Centre

Jack Hirsh, M.D., F.A.C.P., participates in the speakers' bureaus for AstraZeneca Pharmaceuticals LP and Sanofi-Synthelabo Inc. Clive Kearon, M.B., Ph.D., is an advisor to Boehringer Ingelheim and Glaxo-SmithKline.

January 2007

Venous thromboembolism (VTE), a term that encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality in hospitalized and nonhospitalized patients.1,2,3

Risk Factors and Etiology

Most patients with VTE have one or more clinical risk factors. The most common risk factors in hospitalized 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.2,4 The 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.2,3,5 Less common risk factors are paroxysmal nocturnal hemoglobinuria, nephrotic syndrome, and polycythemia vera.

Classification

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 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. Superficial thrombophlebitis may be associated with DVT, which typically is clinically silent. Thrombosis involving the deep veins of the leg may be 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 symptomatic PE. About 25% of calf vein thrombi, however, extend into the popliteal vein and beyond, where they can cause serious complications.6 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.

Pulmonary embolism is the most serious and most feared complication of venous thrombosis, but the postthrombotic syndrome is responsible for greater morbidity. 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, with most cases developing within 2 years of the acute event.4,7 Clinically, the postthrombotic syndrome typically presents as chronic leg pain that is associated with edema and worsens at the end of the day. Some patients also have stasis pigmentation, induration, and skin ulceration; a smaller number of patients have venous claudication on walking, caused by persistent obstruction of the iliac veins. In some cases, the onset of symptoms can be rapid and may mimic recurrent acute venous thrombosis.

Pathophysiology

Venous thrombi are composed predominantly of fibrin and red blood cells.8 They usually arise at sites of vessel damage, the large venous sinuses of the calves, or the valve cusp pockets in the deep veins of the calves. Thrombosis occurs when blood coagulation overwhelms the natural anticoagulant mechanisms and the fibrinolytic system. Coagulation is usually triggered when blood is exposed 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. Malignant cells are rich in tissue factor that activates factor VII and initiates blood coagulation. Venous stasis and damage to the vessel wall increase the thrombogenic effect of blood coagulation. 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 exemplified by the observation that thrombosis occurs with equal frequency in the two legs in paraplegic patients but occurs with much greater frequency in the paralyzed limb than in the nonparalyzed limb in stroke patients.8

Tissue damage also results in impaired fibrinolysis, triggered by the release of inflammatory cytokines in response to the damage. These cytokines induce endothelial cell synthesis of plasminogen activator inhibitor-1 (PAI-1). In addition, they reduce the protective effect of the vascular endothelium by downregulating the endothelial-Bound anticoagulant thrombomodulin.

Increased central venous pressure, which produces venous stasis in the extremities, may explain the high incidence of VTE in patients with heart failure. Stasis resulting from venous dilatation occurs in elderly patients, in patients with varicose veins, and in women who are pregnant or using supplemental estrogen, and may contribute to the increased incidence of thrombosis in these persons. 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 inhibitors or by endothelial cell-Bound inhibitors. The most important circulating inhibitors of coagulation are antithrombin, protein C, and protein S.9,10 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.11 Some types of congenital dysfibrinogenemias can also predispose to thrombosis, as can a congenital deficiency of plasminogen. An inherited thrombophilic defect known as activated protein C (APC) resistance, or factor V Leiden, is the most common cause of inherited thrombophilia. It occurs 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.12,13 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.14 This mutation is found in about 2% of whites who have 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. The risk of thrombosis in patients with thrombophilic defects is increased through the use of estrogen-containing oral contraceptives.15 Randomized trials have shown that the administration of estrogens in the doses used for postmenopausal hormone replacement therapy increases the risk of a first or recurrent thromboembolism about threefold, with the highest risk occurring within the first six months of starting therapy.16,17,18

Natural History and Prognosis

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.6 Complete lysis of proximal vein thrombi is less common. Most symptomatic pulmonary emboli and virtually all fatal emboli arise from thrombi in the proximal veins of the legs. Extensive venous thrombosis causes local valvular damage, which is thought to lead to the postthrombotic syndrome.7 Patients with a history of VTE are more likely to experience additional episodes, particularly if they are exposed to high-risk situations.2,6

Untreated or inadequately treated VTE is associated with a high rate of complications. About 25% of untreated calf-vein thrombi extend into the popliteal vein, and about 50% of untreated proximal-vein thrombi also undergo extension. Patients with proximal-vein thrombosis who are inadequately treated have a recurrence rate of about 40%,19 and patients with symptomatic calf-vein thrombosis treated with a 5-day course of intermittent intravenous heparin without continuation of oral anticoagulant therapy had a recurrence rate greater than 20% over the following 3 months.20

Table 1 Model for Determining Clinical Suspicion of Deep Vein Thrombosis47

Variables

Points*

Active cancer (treatment ongoing or within previous 6 months or palliative)

1

Paralysis, paresis, or recent plaster immobilization of the lower extremities

1

Recently bedridden for more than 3 days, or major surgery within the past 4 weeks

1

Localized tenderness along the distribution of the deep venous system

1

Entire leg swollen

1

Affected calf 3 cm greater than asymptomatic calf (measured 10 cm below tibial tuberosity)

1

Pitting edema confined to the symptomatic leg

1

Dilated superficial veins (nonvaricose)

1

Alternative diagnosis is at least as likely as that of deep vein thrombosis

-2

Total points

 

*Pretest probability is calculated as follows: total points, ≤ 0, low probability; 1 to 2, moderate probability; ≥ 3, high probability.
DVT - deep vein thrombosis

Complications can be markedly decreased by adequate anticoagulant therapy. Fewer than 3% of patients who have proximal-vein thrombosis experience a clinically detectable recurrence during the initial period of treatment with high-dose heparin or low molecular weight heparin (LMWH), and fewer than 3% of patients experience a recurrence during the subsequent 3 months if they are receiving oral anticoagulant therapy or moderate-dose subcutaneous heparin therapy.21 After 3 months of anticoagulant therapy, patients have a risk of recurrence of about 3% in the first year after stopping treatment if their thrombosis developed after a reversible provocation, such as surgery; the recurrence risk is as high as 15% in the first year if the thrombosis was unprovoked or was associated with ongoing conditions, such as prolonged immobilization or cancer.6,13,22,23,24,25,26,27 The recurrence rate is significantly higher after a 4- or 6-week course of warfarin treatment, compared with a 3- or 6-month course.23,25,28 Additional risk factors for recurrent VTE include proximal versus isolated distal thrombosis; an antiphospholipid antibody; and male gender.6,29,30 Hereditary thrombophilias appear to be weak risk factors for recurrent VTE.13,22,31,32,33

Diagnosis

Deep Venous Thrombosis

Clinical Features

The clinical features of DVT, such as localized swelling, redness, tenderness, and distal edema, are nonspecific, and the diagnosis should always be confirmed by objective tests.

About 85% of ambulatory patients with clinically suspected DVT have another cause for their symptoms. 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. Of the patients who actually have DVT, about 85% have proximal vein thrombosis; for the rest, thrombosis is confined to the calf.6,34

Although clinical features cannot unequivocally confirm or exclude a diagnosis of DVT, clinical assessment can stratify the probability of DVT as high (prevalence of thrombosis ~ 60%), intermediate (prevalence ~ 25%), or low (prevalence ~ 5%) on the basis of the following: (1) the presence or absence of risk factors (e.g., recent immobilization, hospitalization within the past month, or malignancy); (2) whether the clinical manifestations at presentation are typical or atypical, and their severity; and (3) whether there is an alternative explanation for the symptoms that is at least as likely as DVT [see Table 1].35

Diagnostic Testing

Four objective tests have been well validated for the diagnosis of DVT: venography, impedance plethysmography (now rarely used), venous ultrasonography, and D-dimer testing.34,36 Magnetic resonance imaging and computed tomography also appear to be accurate tests, but they have not been as thoroughly evaluated.

Venography

Venography, which involves the injection of a radiocontrast agent into a distal vein, is the reference standard for the diagnosis of DVT [seeFigure 1]. Venography detects both proximal-vein thrombosis and calf-vein thrombosis. However, this test is technically difficult and expensive, can be painful, and requires injection of radiographic contrast, which can cause allergic reactions or renal impairment. For these reasons, venography is usually reserved for resolution of any discrepancies between the findings on venous ultrasonography and the clinical assessment of the probability of DVT, or when venous ultrasonography is nondiagnostic (as often occurs in patients with a history of DVT).

 

Figure 1. Venogram: Filling Defects in Left Iliac Vein

Filling defects in the left iliac vein, apparent in this venogram, reveal the presence of thrombi.

Venous ultrasonography

Venous ultrasonography is the noninvasive imaging method of choice for diagnosing DVT.34 It is not painful and is easy to perform. The common femoral vein, superficial 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 the identification of veins.

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 highly operator dependent. For this reason, many centers do not examine the deep veins of the calf with ultrasonography. Instead, if an initial test result excludes proximal DVT and clinical assessment for DVT is moderate or high, the test is repeated in 7 days to detect the small number of calf-vein thrombi that extend to the proximal veins after the initial presentation. If the test remains negative after 7 days, the risk that a thrombus is present and will subsequently extend to the proximal veins is negligible, and it is safe to withhold treatment.34

Ultrasonography is accurate when its results are concordant with clinical assessment; its accuracy drops if the results of these two assessments do not agree. Therefore, if the 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 scan is normal [see Table 2]. In asymptomatic patients who have had elective hip or knee replacement, the sensitivity of ultrasonography for proximal DVT is only about 60%34; such screening is not recommended.

D-dimer blood testing

D-dimer is formed when cross-linked fibrin in thrombi is broken down by plasmin; thus, low levels of D-dimer can be used to exclude DVT and PE. A variety of D-dimer assays are available, and they vary markedly in their accuracy as diagnostic tests for venous thromboembolism.36,37

All D-dimer assays have low specificity for DVT; an abnormal result is associated with a low positive predictive value and cannot be used to diagnose DVT. D-dimer assays that are used for the diagnosis of VTE can be divided into two groups on the basis of their sensitivity and specificity. Very highly sensitive D-dimer assays (e.g., sensitivity ≥ 98%; specificity ~ 40%) have a sufficiently high negative predictive value (≥ 98%) that a normal result can be used to exclude VTE without the need to perform additional diagnostic testing.36,37,38 By contrast, a negative result on one of the moderate to highly sensitive D-dimer assays (sensitivity 85% to 97%; specificity 50% to 70%) needs to be combined with another assessment that identifies patients as having a lower likelihood of VTE in order to exclude DVT or PE. Management studies have shown that it is safe to withhold anticoagulant therapy and not necessary to repeat testing after 1 week to detect extending DVT in patients who have a normal result on a moderately sensitive D-dimer test in combination with (1) a low clinical suspicion for DVT or (2) a normal result on venous ultrasonography of the proximal veins [see Table 2].36,37,39,40 D-dimer testing is much less specific and, therefore, has less clinical utility (i.e., fewer negative tests among those without venous thrombosis) in postoperative and hospitalized patients and the elderly. Also, D-dimer testing has less clinical utility in patients in whom there is a high clinical suspicion of VTE, because negative results are rarely obtained and because the predictive value of a negative test is lower in this group—both factors attributable to the high prevalence of disease in such cases.

Recurrent Deep Venous Thrombosis

The diagnosis of acute recurrent DVT can be difficult.34 A negative D-dimer test can exclude recurrent DVT, although the safety of this approach in recurrent disease has been less well evaluated than for first episodes of DVT.41 If D-dimer testing is positive, or has not been done, venous ultrasonography is performed. If the result is normal, the test should be repeated twice over the next 7 to 10 days. If the result on retesting is positive in the popliteal or common femoral vein segments and the result of the previous test was negative at the same site, a recurrence is diagnosed. Recurrence can also be diagnosed if venous ultrasonography shows other convincing evidence of more extensive thrombosis than was seen on previous examination (e.g., an increase in thrombus diameter of > 4 mm at the inguinal ligament or the midpopliteal fossa; or an unequivocal extension within the femoral vein of the thigh).34,42

Table 2 Test Results That Effectively Confirm or Exclude Deep Vein Thrombosis

Purpose

Test

Significant Result

Diagnostic for first DVT

Venography

Intraluminal filling defect

Venous ultrasonography

Noncompressible proximal veins at two or more of the common femoral, popliteal, and calf trifurcation sites*

Excludes first DVT

Venography

All deep veins seen, and no intraluminal filling defects

D-dimer

Normal value on a test that has at least a moderately high sensitivity (≥ 85%) and specificity (≥ 70%) and (1) normal results on venous ultrasonography of the proximal veins or (2) low clinical suspicion of DVT at presentation Negative result on a test that has a high sensitivity (≥ 98%)

Venous ultrasonography

Normal proximal veins and (1) low clinical suspicion for DVT at presentation, (2) normal D-dimer test at presentation, or (3) normal second test after 7 days
Normal proximal and distal veins*

Diagnostic for recurrent DVT

Venography

Intraluminal filling defect

Venous ultrasonography

(1) A new noncompressible common femoral or popliteal vein segment or (2) a ≥ 4.0mm increase in diameter of the common femoral or popliteal vein since a previous test

Excludes recurrent DVT

Venography

All deep veins seen and no intraluminal filling defects

Venous ultrasonography

Normal or ≤ 1 mm increase in diameter of the common femoral or popliteal veins on venous ultrasound since a previous test and continuing normal results (no progression on venous ultrasound) at 2 and 7 days

D-dimer

Results as described as for a first episode of DVT; however, these criteria are less well evaluated for diagnosis of recurrence

*The diagnostic accuracy of isolated distal vein abnormalities that are detected on ultrasound—and the need to treat such abnormalities—is uncertain. For this reason, and because examination of the calf veins is difficult to perform, many centers confine the examination to the proximal veins.
If other evidence is not consistent with recurrent DVT (e.g., clinical assessment or D-dimer), venography should be considered.
DVT—deep vein thrombosis

If findings on venous ultrasonography are equivocal, as compared with a previous scan, or a previous scan is not available for comparison, either venography should be performed or the ultrasound examination repeated twice over the next 7 to 10 days to detect extension of thrombosis. If the venogram shows a new intraluminal filling defect or evidence of thrombus extension since a previous venogram, recurrent DVT is diagnosed. If the venogram outlines all of the deep veins and does not show an intraluminal filling defect, recurrent DVT is excluded. If the venogram is nondiagnostic (i.e., nonfilling of segments of the deep veins), the patient can be followed with repeat venous ultrasonography (as described above), or recurrent DVT can be diagnosed on the basis of the results of all assessments, including clinical features [see Table 2].

Pulmonary Embolism

Clinical Features

Dyspnea is the most common symptom of PE. Chest pain is also common; it is usually pleuritic but can be substernal and compressive. Tachycardia is relatively common, while hemoptysis is less frequent. Although most patients with PE also have DVT, fewer than 25% have clinical features of thrombosis.43,44,45 However, the clinical features of PE, like those of DVT, are nonspecific, and in only about one quarter of symptomatic patients is the diagnosis confirmed by objective tests.

In the past, clinical assessment of the probability of PE was not standardized; physicians made the assessment informally on the basis of their experience and the results of initial routine tests (e.g., chest x-ray and electrocardiogram).43,45 Two groups have published explicit criteria for determining the clinical probability of PE.46,47,48,49 The model created by Wells and colleagues incorporates an assessment of symptoms and signs, the presence of an alternative diagnosis to account for the patient's condition, and the presence of risk factors for VTE.47,48,49 Using this model, it is possible to categorize the clinical probability of PE in a particular patient as low or unlikely (prevalence < 10%), moderate (prevalence ~ 25%), or high (prevalence of 60%) [see Table 3].47,48,49

Diagnostic Tests

Chest radiography and electrocardiography

In patients with PE, chest x-rays show either normal or nonspecific findings. Chest radiography, however, is useful for exclusion of pneumothorax and other conditions that can simulate PE. The ECG also frequently shows normal or nonspecific findings, but it is valuable for excluding acute myocardial infarction. In the appropriate clinical setting, ECG evidence of right ventricular strain suggests PE.

Ventilation-perfusion lung scanning

In the past, ventilation-perfusion lung scanning was the most important test for diagnosing PE [see Figure 2].43 More recently, however, computed tomographic pulmonary angiography (CTPA) has supplanted lung scanning, although lung scanning is still used, particularly when CTPA is contraindicated because of renal failure or associated radiation exposure to the chest (e.g., in young women). A normal perfusion scan excludes a diagnosis of PE. However, a normal result is obtained in only about 25% of consecutive patients (this percentage is higher in patients who are young, who do not have chronic lung disease, or who have an abnormal chest radiograph at presentation). An abnormal perfusion scan is nonspecific [see Table 4].

Table 3 Model for Determining a Clinical Suspicion of Pulmonary Embolism48

Variables

Points*

Clinical signs and symptoms of deep vein thrombosis (minimum leg swelling and pain with palpation of the deep veins)

3.0

An alternative diagnosis is less likely than pulmonary embolism

3.0

Heart rate > 100 beats/min

1.5

Immobilization or surgery in the previous 4 weeks

1.5

Previous deep vein thrombosis/pulmonary embolism

1.5

Hemoptysis

1.0

Malignancy (treatment ongoing or within previous 6 months or palliative)

1.0

Total points

 

*Pretest probability is calculated as follows: a total score of ≤ 4 indicates a low probability (also termed “unlikely”); a score of 4.5 to 6 indicates moderate probability; and a score of > 6 indicates high probability.

Ventilation imaging improves the specificity of perfusion scanning for the diagnosis of PE, particularly when the ventilation scan is normal at the site of a large or segmental perfusion defect, a finding that is associated with an 85% or higher likelihood of PE (termed a high-probability lung scan).43 About half of patients who have PE have a high-probability lung scan. Therefore, among consecutive patients who are investigated for PE, about 25% have a normal perfusion scan and can have the diagnosis excluded, about 15% have a high-probability scan and can be diagnosed with PE (provided the clinical probability is not low), and about 60% have an abnormal but nondiagnostic lung scan that requires further diagnostic testing.43

 

Figure 2. Perfusion Scans Showing Multiple Perfusion Defects

Posterior, right posterior oblique, and left posterior oblique perfusion scans (top), which were developed by using radiopharmaceutical technetium-99m (99mTc) microspheres of albumin, show multiple large perfusion defects, particularly involving the right lung. Ventilation scans (bottom) of the same projections, made with the patient breathing krypton-81m (81mKr), show that ventilation was well maintained compared to perfusion. The presence of multiple segmental perfusion defects with associated normal ventilation (best seen in the right lung) indicated a “high probability” lung scan and is diagnostic for pulmonary embolism.

Computed tomographic pulmonary angiography

Computed tomographic pulmonary angiography (CTPA), performed using helical CT (also known as spiral or continuous-volume CT), can directly visualize the pulmonary arteries [see Figure 3]. Helical CT technology has rapidly advanced from the use of single-detector scanners to the use of progressively larger numbers of detectors (termed multidetector CT) that allow more detailed examination of the pulmonary arteries.

Current evidence from the PIOPED II study suggests that CTPA is nondiagnostic in 6% of patients, and that among adequate examinations, the sensitivity for PE is 83%, specificity is 96%, positive predictive value is 86%, and negative predictive value is 95%.50 Accuracy varies according to the size of the largest pulmonary artery involved: the positive predictive value was 97% for pulmonary emboli in the main or lobar artery, 68% for emboli in segmental arteries, and 25% for those in subsegmental arteries (4% of pulmonary emboli in this study). Predictive values were also influenced by clinical assessment of the probability of PE. The positive predictive value of CTPA was 96% when the clinical probability was high, 92% when it was intermediate, and 58% when the probability was low (8% of patients). The negative predictive value was 96% when the clinical probability was low, 89% when it was intermediate, and 60% when it was high (3% of patients).

The ability of CTPA to exclude PE has also been evaluated in management studies in which anticoagulant therapy was withheld in patients with negative CTPA. More recent studies suggest that fewer than 2% of patients with a negative CTPA for PE will return with symptomatic VTE during follow-up.49,51,52 Taken together, these observations suggest the following conclusions [see Figure 4]:

  1. An intraluminal filling defect in a lobar or larger pulmonary artery is generally diagnostic for PE. However, if the clinical probability is low and if there are additional findings that undermine a diagnosis of PE (e.g., a technically suboptimal study or a negative D-dimer test), further diagnostic testing should be considered (e.g., venous ultrasonography, ventilation-perfusion scanning, repeat CTPA, or conventional pulmonary angiography).
  2. A good-quality negative CTPA excludes PE provided there is not a high clinical suspicion for PE. If clinical suspicion is high or if the CTPA is suboptimal, imaging of the proximal deep veins of the legs should be performed to exclude DVT.
  3. Intraluminal filling defects that are confined to segmental pulmonary arteries are generally diagnostic for PE if the clinical suspicion is moderate or high, but they should be considered nondiagnostic if the clinical suspicion is lower or if there are additional findings that undermine a diagnosis of PE (see above).
  4. Intraluminal defects that are confined to subsegmental pulmonary arteries are generally nondiagnostic and require further investigation.

Table 4 Test Results that Effectively Confirm or Exclude Pulmonary Embolism43

Conclusion

Test

Result

Diagnostic for PE

Pulmonary angiography

Intraluminal filling defect

CT pulmonary angiography

Intraluminal filling defect in a segmental, lobar, or main pulmonary artery

Ventilation-perfusion scan

High-probability scan and moderate/high clinical probability

Tests for DVT*

Evidence of acute DVT with nondiagnostic ventilation-perfusion scan or CT pulmonary angiograrn

Excludes PE

Pulmonary angiography

Normal

CT pulmonary angiography

Negative

Lung perfusion scan

Normal

High-sensitivity D-dimer test

Negative

Moderate-sensitivity D-dimer test§

Negative, plus (1) low clinical suspicion of PE or (2) normal alveolar dead space fraction or (3) nondiagnostic lung scan and negative ultra-sonography of proximal leg veins

Combination of clinical assessment, ventilation-perfusion scan, ultrasonography of proximal leg veins

Low clinical suspicion, nondiagnostic scan, and negative ultrasonography

*See Table 2.
If clinical suspicion is high, supplemental bilateral ultrasonography of the proximal leg veins is recommended.
D-dimer assay with very high sensitivity (i.e. 98%) and at least moderate specificity (i.e., 40%).
§D-dimer assay with at least moderately high sensitivity (i.e., 85%) and specificity (i.e., 70%).
DVT—deep vein thrombosis   PE—pulmonary embolism

Magnetic resonance imaging (MRI)

Magnetic resonance imaging is less well evaluated than helical CT for the diagnosis of PE but is expected to be less accurate. Both helical CT and MRI have the advantage of being able to identify alternative pulmonary diagnoses. MRI does not expose the patient to radiation or radiographic contrast media. Both MRI and helical CT can be extended to look for concomitant DVT.

D-dimer blood testing

D-dimer testing is also a valuable test for the exclusion of PE, either when used alone (very sensitive D-dimer assay) or when combined with other assessments that indicate a reduced likelihood of PE [see Figure 4].48,51,52,53

Compression ultrasonography

Compression ultrasonography to evaluate the proximal deep veins of the legs can aid in the diagnosis of PE. Demonstration of DVT, which occurs in about 5% of patients with nondiagnostic ventilation-perfusion lung scans, can serve as indirect evidence of PE. Exclusion of proximal DVT does not rule out PE in a patient with a nondiagnostic ventilation-perfusion scan, although it somewhat reduces the probability of that diagnosis. However, if there are no proximal deep vein thrombi on the day of presentation and if none are detected on two subsequent examinations one and two weeks later (DVT is diagnosed during serial testing in ~2% of patients), anticoagulant therapy can be withheld with a very low risk that patients will return with VTE (less than 2% during 3 months of follow-up).52,53,54

 

Figure 3. CTPA Showing Intraluminal Filling Defects

Computed tomographic pulmonary angiography (CTPA) demonstrates intraluminal filling defects caused by pulmonary embolism in the lobar artery of the left lower lobe (small arrow) and the main artery of the right lung (large arrow) in a patient with a chest deformity.

 

Figure 4. Diagnostic Approach to Pulmonary Embolism

Algorithm outlines a diagnostic approach to pulmonary embolism. Use of a very sensitive D-dimer assay can obviate clinical assessment: A negative result excludes PE regardless of the results of the clinical assessment. However, the yield from D-dimer testing is low in patients in whom there is a high clinical suspicion of pulmonary embolism. A positive finding on the D-dimer assay can be followed by CT pulmonary angiography (CTPA). If the D-dimer assay is expected to be positive in the absence of PE (e.g., in a postoperative patient), CTPA can be performed as the initial objective test.

*Ultrasonography of the proximal deep veins of both legs is recommended to detect asymptomatic DVT if the clinical assessment indicates a high probability of PE. (DVT—deep vein thrombosis; PE—pulmonary embolism; VTE—venous thromboembolism)

Earlier studies that evaluated CTPA suggested that a negative result did not exclude PE and, therefore, this exam should be followed by bilateral ultrasonography of the proximal veins. However, more recent studies of CTPA—conducted primarily with multidetector scanners—do not support the need for routine ultrasonography of the proximal deep veins in patients with a negative CTPA.49,51 Instead, it appears to be reasonable to perform ultrasonography of the proximal deep veins only if clinical suspicion for PE is high. As for patients with nondiagnostic ventilation-perfusion lung scans, withholding of anticoagulant therapy and performance of serial ultrasonography is a reasonable approach to the management of those patients who have a CTPA that is suspicious for isolated subsegmental pulmonary embolism.

Pulmonary angiography

Pulmonary angiography had been considered the reference standard for the diagnosis of PE but is now rarely performed because it is invasive and can usually be replaced by CTPA. Pulmonary angiography can be complicated by arrhythmias, cardiac perforation, cardiac arrest, and hypersensitivity to the contrast medium. Complications occur in 3% to 4% of patients undergoing pulmonary angiography. Various combinations of test results can be used to either confirm or exclude a diagnosis of PE [see Table 4].

Prophylaxis and Treatment

Pharmacology of Anticoagulant Agents

A less intense anticoagulant effect is required for the prevention of VTE than is required for its treatment. The anticoagulants in clinical use are heparin, LMWH, and fondaparinux, which are administered subcutaneously or intravenously; and coumarin compounds, which are given orally. Thrombolytic agents that are most commonly used for treatment of VTE are streptokinase and recombinant tissue plasminogen activator (rt-PA).

Heparin and LMWH

Heparin is a highly sulfated glycosaminoglycan that produces its anticoagulant effect by binding to antithrombin, markedly accelerating the ability of the naturally occurring anticoagulant to inactivate thrombin, activated factor X (factor Xa), and activated factor IX (factor IXa).55At therapeutic concentrations, intravenous heparin has a half-life of about 60 minutes. Its clearance is dose dependent. Heparin has decreased bioavailability when administered subcutaneously in low doses but has approximately 90% bioavailability when administered in high therapeutic doses.

Heparin binds to a number of plasma proteins, a phenomenon that reduces the anticoagulant effect of heparin by limiting its accessibility to antithrombin. The concentration of heparin-Binding proteins increases during illness, contributing to the variability in anticoagulant response in patients with thromboembolism.55 Because of this variability, response to heparin should be monitored with the activated partial thromboplastin time (aPTT). The dose should be adjusted as necessary to achieve a therapeutic range, which for many aPTT reagents corresponds to an aPTT ratio of 1.8 to 2.5. A recent study showed that fixed, weight-adjusted, subcutaneous heparin was as effective and safe as LMWHs in patients with acute VTE.56 This finding questions the need for laboratory monitoring of heparin when the anticoagulant is given subcutaneously in currently recommended weight-adjusted doses.

LMWHs are effective in the prevention and treatment of VTE. They are derived from standard commercial-grade heparin by chemical depolymerization to yield fragments approximately one third the size of heparin.55 Depolymerization of heparin results in a change in its anticoagulant profile, bioavailability, and pharmacokinetics and in a lower incidence of heparin-induced thrombocytopenia and of osteopenia.55 The plasma recoveries and pharmacokinetics of LMWHs differ from those of heparin because LMWHs bind much less avidly to heparin-Binding proteins than does heparin. This property of LMWHs contributes to their superior bioavailability at low doses and their more predictable anticoagulant response. LMWHs also exhibit less binding to macrophages and endothelial cells than does heparin, a property that accounts for their longer plasma half-life (approximately 3 hours) and their dose-independent clearance. These potential advantages over heparin permit once-daily administration of LMWHs without laboratory monitoring and have led to the successful treatment of DVT, and of selected patients with PE, outside the hospital setting. The published research on LMWHs, which includes over 5,000 patients treated with either once-daily or twice-daily subcutaneous doses, has established this class of anticoagulants as safe, effective, and convenient for treating DVT and PE.21,57 LMWH, given once daily, has been shown to be more effective than warfarin for the first 3 to 6 months of treatment of VTE in patients with cancer.58,59

Fondaparinux

Fondaparinux is a new parenteral synthetic anticoagulant composed of the five saccharide units that make up the active site of heparin that binds antithrombin.60 The fondaparinux-antithrombin complex inhibits factor Xa but has no direct activity against thrombin. Fondaparinux is rapidly absorbed and is 100% bioavailable when administered subcutaneously. It is not metabolized, is renally excreted, and has a dose-independent elimination half-life of 15 hours, which makes it suitable for once-daily administration. Fondaparinux has been shown to be effective for prevention and treatment of VTE.61,62,63

Vitamin K antagonists

Oral anticoagulants such as coumarin compounds, the most common of which is warfarin, achieve their anticoagulant effect by producing hemostatically defective, vitamin K-dependent coagulant proteins (prothrombin, factor VII, factor IX, and factor X).64

The dose of warfarin must be monitored closely because the anticoagulant response varies widely among individuals. Laboratory monitoring is performed by measuring the prothrombin time (PT), a test responsive to depression of three of the four vitamin K-dependent clotting factors (prothrombin and factors VII and X). Commercial PT reagents vary markedly in their responsiveness to warfarin-induced reduction in clotting factors, but this variability problem has been overcome by the introduction of the international normalized ratio (INR).64

The starting dose of warfarin has traditionally been 10 mg, with an average maintenance dose of about 5 mg. However, the dose required varies widely among individuals. For example, elderly patients and women have been shown, on average, to require lower doses. A starting dose of 5 mg rather than 10 mg is preferable in most inpatients. Warfarin therapy is difficult to manage in some patients because of unexpected fluctuations in dose response, which may reflect changes in diet, inaccuracy in PT testing, undisclosed drug use, poor compliance, or surreptitious self-medication. Certain over-the-counter and prescription drugs can augment or inhibit the anticoagulant effect of coumarin compounds or prolong hemostasis by interfering with platelet function [see Table 5].

Patients receiving coumarin compounds are also sensitive to fluctuating levels of dietary vitamin K, which is obtained predominantly from leafy green vegetables. The effect of coumarins can be potentiated in sick patients with poor vitamin K intake, particularly if they are treated with antibiotics and intravenous feeding without vitamin K supplementation, and in states of fat malabsorption.

New anticoagulants

Direct thrombin inhibitors (e.g., bivalirudin, hirudin, ximelagatran) have been shown to be effective for prevention and treatment of VTE.60,65 Ximelagatran, however, is associated with liver toxicity, which has prevented its use in clinical practice, and bivalirudin is being marketed for percutaneous coronary intervention. Hirudin and another direct thrombin inhibitor, called argatraban, are indicated for heparin-induced thrombocytopenia. A number of new compounds, including new direct antithrombins and inhibitors of other clotting factors, are at advanced stages of development.60

Complications of Antithrombotic Agents

Bleeding is the main complication of antithrombotic therapy.66 With all antithrombotic agents, the risk of bleeding is influenced by the dose and by patient-related factors, the most important of which is recent surgery or trauma. Other patient characteristics that increase the risk of bleeding are older age, recent stroke, generalized hemostatic defect, a history of gastrointestinal hemorrhage, renal failure, and other serious comorbid conditions.

With heparin, the incidence of bleeding is influenced by dosage; independently of dosage, there is no clear relationship between bleeding and the aPTT.55,66 Bleeding rates appear to be lower with LMWH than with intravenous heparin.21

Bleeding associated with coumarin anticoagulants is influenced by the intensity of anticoagulant therapy, particularly with progressive increases of the INR above 3.0.66 A study that compared long-term treatment of VTE with warfarin targeted to an INR of 1.75 versus an INR of 2.5 found no difference in the bleeding rates, suggesting that differences in the INR between 1.5 and 3.0 are not associated with clinically important differences in bleeding risk.67 Both heparin-induced bleeding and warfarin-induced bleeding are increased by concomitant use of aspirin, which impairs platelet function and produces gastric erosions. When the INR is less than 3.0, coumarin-associated bleeding frequently has an obvious underlying cause or is from an occult gastrointestinal or renal lesion.

Table 5 Drug and Food Interactions with Warfarin by Strength of Supporting Evidence and Direction of Interaction105

Level of Causation

Anti-Infectives

Cardiovascular Drugs

Analgesics, Anti-inflammatories and Immunologics

CNS Drugs

GI Drugs and Food

Herbal Supplements

Other Drugs

Potentiation*


Highly probable

Ciprofloxacin, cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, miconazole (oral), miconazole (vaginal), voriconazole

Amiodarone, clofibrate, diltiazem, fenofibrate, propafenone, propranolol, sulfinpyrazone

Phenylbutazone, piroxicam

Alcohol (with liver disease), citalopram, entacapone, sertraline

Cimetidine, fish oil, mango, omeprazole

Boldofenugreek, quilinggao

Anabolic steroids, zileuton

Probable

Amoxicillinclavulanate, azithromycin, clarithromycin, itraconazole, levofloxacin, ritonavir, tetracycline

Acetylsalicylic acid, fluvastatin, quinidine, ropinirole, simvastatin

Acetaminophen, acetylsalicylic acid, celecoxib, dextropropoxyphene, interferon, tramadol

Chloral hydrate, disulfiram, fluvoxamine, phenytoin

Grapefruit juice

Danshen, dong quai, Lycium barbarum, PC-SPES

Fluorouracil, gemcitabine, levamisole/fluorouracil, paclitaxel, tamoxifen, tolterodine

Inhibition*

Highly probable

Griseofulvin, nafcillin, ribavirin, rifampin

Cholestyramine

Mesalamine

Barbiturates, carbamazepine

High vitamin K foods/enteral feeds, avocado

Mercaptopurine

Probable

Dicloxacillin, ritonavir

Bosentan

Azathioprine

Chlordiazepoxide

Soy milk, sucralfate

Ginseng

Chelation therapy, influenza vaccine, multivitamin supplement, raloxifene hydrochloride

*Interactions for which there is “possible” supporting evidence are not included in this table, Although there is strong evidence that some drugs and foods do not interact with warfarin,105 in general, caution and a higher frequency of INR monitoring is recommended whenever patients on warfarin start (or stop) a new medication,

Nonhemorrhagic side effects of heparin include: (1) urticaria at sites of subcutaneous injection; (2) thrombocytopenia, which occurs in about 1% of patients treated with high-dose heparin and is complicated by arterial or venous thrombosis in about 0.2% of treated patients [see 5:XIV Thrombotic Disorders]; (3) osteoporosis, which occurs with prolonged high-dose heparin use; and, rarely, (4) alopecia, adrenal insufficiency, and skin necrosis. The incidence of thrombocytopenia is lower with LMWH than with heparin. Similarly, there is evidence that the risk of osteopenia is lower with LMWH than with heparin.55

The most important nonhemorrhagic side effect of coumarin anticoagulants is skin necrosis, an uncommon complication usually observed on the third to eighth day of therapy. Skin necrosis is caused by extensive thrombosis of the venules and capillaries within the subcutaneous fat. An association has been reported between coumarin-induced skin necrosis and protein C deficiency—and, less commonly, protein S deficiency—but this complication can also occur in patients without these deficiencies.

Primary Prophylaxis

The most effective way to reduce the mortality associated with PE and the morbidity associated with the postthrombotic syndrome is to institute primary prophylaxis in patients at risk for VTE. On the basis of well-defined clinical criteria, patients can be classified as being at low, moderate, or high risk for VTE, and the choice of prophylaxis should be tailored to the patient's risk [see Table 6]. In the absence of prophylaxis, the frequency of fatal postoperative PE ranges from 0.1% to 0.4% in patients undergoing elective general surgery and from 0.4% to 5% in patients undergoing elective hip or knee surgery, emergency hip surgery or surgery for major trauma or spinal cord injury. Prophylaxis is cost-effective for most high-risk groups.68

Prophylaxis is achieved either by modulating activation of blood coagulation or by preventing venous stasis by using the following proven approaches: low-dose subcutaneous heparin, intermittent pneumatic compression of the legs, coumarin anticoagulants, adjusted doses of subcutaneous heparin, graduated compression stockings, LMWHs, or fondaparinux.61,68 Antiplatelet agents, such as aspirin, also prevent VTE but are less effective than the previously stated methods.68,69

Low-dose heparin is given subcutaneously at a dose of 5,000 units (U) 2 hours before surgery and 5,000 U every 8 or 12 hours after surgery. In patients undergoing major orthopedic surgical procedures, low-dose heparin is less effective than warfarin, LMWH, or fondaparinux. Intermittent pneumatic compression of the legs enhances blood flow in the deep veins and increases blood fibrinolytic activity. This method of prophylaxis is free of clinically important side effects and is particularly useful in patients who have a high risk of serious bleeding. It is the method of choice for preventing venous thrombosis in patients undergoing neurosurgery, is effective in patients undergoing major knee surgery, and is as effective as low-dose heparin in patients undergoing abdominal surgery.

Table 6 Risk Categories for Venous Thromboembolism and Recommendations for Prophylaxis

 

High Risk

Moderate Risk

Calf vein thrombosis
Proximal vein thrombosis
Fatal pulmonary embolism

20%–50%
5%–20%
0.4%–5%

10%–20%
2%–5%
0.1%–0.4%

Recommended prophylaxis

Low-molecular-weight heparin, oral anticoagulants, or fondaparinux (can be combined with graduated compression stockings or pneumatic compression)

Low-dose heparin, external pneumatic compression, or graduated compression stockings

Graduated compression stockings reduce venous stasis and prevent postoperative venous thrombosis in general surgical patients and in medical or surgical patients with neurologic disorders, including paralysis of the lower limbs.68 In surgical patients, the combined use of graduated compression stockings and low-dose heparin is more effective than use of low-dose heparin alone. Graduated compression stockings are relatively inexpensive and should be considered in all high-risk surgical patients, even if other forms of prophylaxis are used.

Moderate-dose warfarin (INR = 2.0 to 3.0) is effective for preventing postoperative VTE in patients in all risk categories.68 Warfarin therapy can be started at the time of surgery or in the early postoperative period. Although the anticoagulant effect is not achieved until the third or fourth postoperative day, warfarin is effective in patients at very high risk, including patients with hip fractures and those who undergo joint replacement. Prophylaxis with warfarin is less convenient than that with low-dose heparin, LMWHs, or fondaparinux because careful laboratory monitoring is necessary.

LMWH is a safe and effective form of prophylaxis in high-risk patients undergoing elective hip surgery, major general surgery, or major knee surgery, as well as in patients who have experienced hip fracture, spinal injury, or acute medical illness. LMWH is more effective than standard low-dose heparin in general surgical patients, patients undergoing elective hip surgery, and patients with spinal injury.

In patients who undergo hip or major knee surgery, LMWH is more effective than warfarin but is also associated with more frequent bleeding; both of these properties may be attributable to the more rapid onset of anticoagulation with postoperatively initiated LMWH than with warfarin. It is uncertain whether the superior efficacy of LMWH over warfarin in the prevention of venographically detectable DVT is mirrored by fewer symptomatic episodes of VTE.

Fondaparinux was shown to reduce the frequency of venographically detected DVT by 50% but to cause a small increase in bleeding compared with LMWH in a series of large trials in orthopedic surgical patients.61

Indications for Prophylaxis

General surgery and medicine

Low-dose-heparin or LMWH prophylaxis is the method of choice for moderate-risk general surgical and medical patients. Both approaches are simple, inexpensive, convenient, and safe, and each reduces the risk of VTE by 50% to 70%.68 If anticoagulants are contraindicated because of an unusually high risk of bleeding, graduated compression stockings, intermittent pneumatic compression of the legs, or both should be used. Fondaparinux has also been shown to be effective in these patients.

Major orthopedic surgery

LMWH, fondaparinux, or oral anticoagulants provide effective prophylaxis for VTE in patients who have undergone hip surgery. Aspirin has also been shown to reduce the frequency of symptomatic VTE and fatal PE after hip fracture.69 The relative efficacy and safety of aspirin versus LMWH, fondaparinux, or oral anticoagulants in patients who have a hip fracture or have undergone hip or knee arthroplasty is uncertain. However, because studies have shown that aspirin is much less effective than LMWH or oral anticoagulants at preventing venographically detectable DVT, aspirin is not recommended as the sole agent for postoperative prophylaxis.68

LMWH, warfarin, fondaparinux, and intermittent pneumatic compression are effective in preventing VTE in patients undergoing major knee surgery.

Extended prophylaxis with LWMH or warfarin for an additional 3 weeks after hospital discharge should be considered after major orthopedic surgery. Extended prophylaxis is strongly recommended for high-risk patients (e.g., those with previous VTE or active cancer).68,70

Genitourinary surgery, neurosurgery, and ocular surgery

Intermittent pneumatic compression, with or without graduated compression stockings, is an effective prophylaxis for VTE and does not increase the risk of bleeding.

Treatment

The objectives of treating patients with VTE are to prevent PE, the postthrombotic syndrome, thromboembolic pulmonary hypertension, and recurrent VTE and to alleviate the discomfort of the acute event.

Superficial venous thrombosis usually can be treated conservatively with anti-inflammatory drugs. If superficial phlebitis is extensive or very symptomatic, a 1 to 2 week course of heparin or LMWH therapy can be used. In patients with DVT, anticoagulants can effectively reduce morbidity and mortality from PE.59 Vena caval interruption, which is usually achieved with an inferior vena caval filter, is also effective but is more complicated, expensive, and invasive and is associated with a doubling of the frequency of recurrent DVT during long-term follow-up.71 For these reasons, it is generally used only if anticoagulant therapy has failed or is contraindicated because of the risk of serious hemorrhage.59

Thrombolytic therapy is more effective than heparin in achieving early lysis of venous thromboemboli and is better than heparin for preventing death in patients with massive PE associated with shock.59 Thrombolytic therapy is therefore the treatment of choice for patients with life-threatening PE. A regimen of 100 mg of recombinant tissue plasminogen activator (rt-PA) administered over 2 hours is generally recommended. The role of thrombolytic therapy in the treatment of DVT is uncertain. Systemic thrombolytic therapy increases lysis of DVT, particularly when employed early in the course of treatment, and may reduce the risk of developing the postthrombotic syndrome. However, systemic thrombolytic therapy increases the frequency of major bleeding, including intracranial hemorrhage. Catheter-directed thrombolytic therapy, often combined with mechanical disruption of thrombus and stent insertion if there is residual thrombosis, may be associated with a lower risk of bleeding.59

Thromboendarterectomy is effective treatment in selected cases of chronic thromboembolic pulmonary hypertension involving proximal pulmonary arterial obstruction.72

Routine early use of graduated compression stockings for 2 years has been reported to reduce the incidence of the postthrombotic syndrome by about 50% in some studies.73,74 However, lingering doubts about their efficacy remains, and further evaluation is being performed.

Administration and Dosage Guidelines

Anticoagulant therapy

Anticoagulants are the mainstay of treatment for most patients with VTE. In the past, the treatment of choice was heparin administered by continuous intravenous infusion or subcutaneous injection, in doses sufficient to produce an adequate anticoagulant response. Now many patients are treated with LMWH administered by subcutaneous injection without laboratory monitoring since this class of anticoagulant is as effective and safe as heparin.28

Fondaparinux is as effective and safe as LMWH for the treatment of DVT and as effective and safe as heparin for the treatment of PE.

The anticoagulant effect of intravenous heparin is immediate. With subcutaneous injection, the anticoagulant effect of heparin, LMWH, and fondaparinux is delayed for about an hour; peak levels occur at about 4 hours. The anticoagulant effect of subcutaneous heparin is maintained for about 12 hours with therapeutic doses. LMWH and fondaparinux are effective when administered subcutaneously once daily.21

Heparin therapy is usually monitored by the aPTT and less frequently by heparin assays, which measure the ability of heparin to accelerate the inactivation of factor Xa or thrombin by antithrombin. The starting dose of intravenous heparin is a bolus of 80 U/kg (or a set dose of 5,000 U) followed by an initial infusion of 18 U/kg/hr (or a set dose of about 1,300 U/hr). The anticoagulant effect should be monitored every 6 hours until the aPTT is in the therapeutic range, and then daily. The therapeutic range of aPTT is equivalent to a heparin level between 0.35 and 0.7 U/ml as measured by an anti-factor Xa assay. For many aPTT reagents, this range is an aPTT ratio of 1.8 to 2.5 times the mean of the normal laboratory control value.

A recent study showed that acute VTE can be treated with subcutaneous, weight-adjusted heparin without laboratory monitoring of coagulation (initial dose of 333 U/kg followed by 250 U/kg every 12 hours).56

LMWH is administered subcutaneously on a weight-adjusted basis at a dosage of either 100 anti-Xa U/kg every 12 hours or 150 to 200 anti-Xa units once daily.59 Monitoring is not required.

Treatment with heparin or LMWH is usually continued for 5 to 6 days; warfarin therapy is started on the first or second day, overlapping the heparin therapy (or LMWH) for 4 or 5 days, and is continued until an INR of 2.0 is maintained for at least 24 hours. A 4- to 5-day period of overlap is necessary because the antithrombotic effects of oral anticoagulants are delayed. The initial course of heparin should be followed by warfarin for at least 3 months.59 In patients with unprovoked VTE, administration of low-intensity warfarin (INR = 1.5 to 2.0) after the first 6 months of anticoagulant therapy reduces the risk of recurrent VTE by two thirds; however, low-intensity warfarin is less effective than conventional-intensity warfarin therapy (INR = 2.0 to 3.0) and has not been shown to reduce bleeding.13,75 Low-intensity warfarin therapy has been used with less frequent monitoring of the INR (i.e., about every 2 months). Intermediate to full-dose LMWH can also be used in place of warfarin in the outpatient setting and is preferred to warfarin in patients with active cancer.58,59

Duration of anticoagulant therapy

During the past decade, a series of well-designed studies has helped to define the optimal duration of anticoagulation. The findings of these studies can be summarized as follows:

  • Shortening the duration of anticoagulation from 323,28or 625 months to 423,28,76 or 625 weeks results in a doubling of the frequency of recurrent VTE during 123,28,76 to 225 years of follow-up.
  • Patients with VTE provoked by a transient risk factor have a lower (about one third) risk of recurrence than those with an unprovoked VTE or a persistent risk factor.22,23,25,28,77,78
  • Three months of anticoagulation is adequate treatment for VTE provoked by a transient risk factor; subsequent risk of recurrence is about 3% in the first year of follow-up.22,23,24,28,78,79
  • Three months of anticoagulation may not be adequate treatment for an unprovoked (idiopathic) episode of proximal DVT or PE; subsequent early risk of recurrence is about 10% to 15% in the first year of follow-up.13,22,24,25,26,27
  • After 6 months of anticoagulation, recurrent DVT is at least as likely to affect the contralateral leg; this suggests that systemic rather than local (including inadequate treatment) factors are responsible for recurrences after 6 months of treatment.80
  • There is a persistently elevated risk of recurrent VTE after a first episode of VTE; this appears to be about 10% in the first year, and about 30% in the first 5 years, after 6 or more months of treatment for an unprovoked proximal DVT or PE.22,24,25,26,27
  • Extending duration of anticoagulation beyond 3 to 6 or 12 months may delay, but ultimately not reduce, the risk of recurrence if therapy is then stopped.26,27
  • After 3 months of initial treatment of unprovoked VTE with oral anticoagulants targeted at an INR of 2.5 (INR range 2.0 to 3.0), continuing treatment with:
  • Oral anticoagulants targeted at an INR of ~2.5 reduces the risk of recurrent VTE by over 90%.13,81
  • Oral anticoagulants targeted at an INR of ~1.75 reduces the risk of recurrent VTE by about 75%.75
  • Oral anticoagulants targeted at an INR of ~2.5 are more effective than using an INR target of ~1.75, without evidence of increased bleeding.67
  • A second episode of VTE predicts a higher risk of recurrence but not necessarily high enough to justify indefinite anticoagulation.82,83,84
  • Risk of recurrence is lower (about half) following an isolated calf (distal) DVT than after proximal DVT or PE, and this favors a shorter duration of treatment.24,25
  • Risk of recurrence in patients who discontinue treatment is similar after an episode of either proximal DVT or PE.25,82,85,86
  • About 5% of recurrent episodes of VTE are expected to be fatal.82,85
  • Recurrent VTE is usually (about 60% of episodes) a PE after an initial PE, and usually (about 80% of episodes) a DVT after an initial DVT82,85,87,88; this effect is expected to increase mortality from recurrent VTE by 2- to 3-fold following a PE compared with that following a DVT.89
  • Risk of recurrence is about 3-fold higher in patients with active cancers.77,86,90
  • Long-term treatment with LMWH is more effective than warfarin in patients with VTE associated with cancer and may be a preferred option for such patients.91
  • Estrogen therapy is an important risk factor for first17,92and recurrent18 episodes of VTE; consequently, if VTE occurred while on estrogen therapy, the risk of recurrent VTE is expected to be lowered by stopping estrogens.86
  • Risk of recurrence appears to be higher in patients with antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulants, or both).13,83,88
  • Hereditary thrombophilias, including heterozygous Factor V Leiden and the G20210A prothrombin gene mutations, double heterozygous states for these two genes, homozygous factor V Leiden, homozygous prothrombin gene G20210A, or deficiency of protein C, protein S, or antithrombin, appear to be weak risk factors for recurrent VTE.22,31,32,33,93,94,95
  • Males appear to have about a 50% higher risk of recurrent VTE than females.30
  • Other risk factors for recurrences may include advanced age; elevated levels of clotting factors VIII, IX, XI, and homocysteine; elevated D-dimer levels after stopping anticoagulant therapy; vena caval filters; and residual DVT on ultrasound; currently, these factors do not have clear implications for duration of treatment.89
  • The risk of anticoagulant-induced bleeding is highest during the first 3 months of treatment and stabilizes after the first year.96
  • Risk of bleeding differs markedly among patients depending on the prevalence of risk factors (e.g., advanced age, previous bleeding or stroke, renal failure. anemia, antiplatelet therapy, malignancy, poor anticoagulant control).67,96,97
  • About 10% of episodes of major bleeding are fatal.98
  • The risk of major bleeding in younger patients (e.g., those younger than 60 years) who do not have risk factors for bleeding and have good anticoagulant control (target INR 2.0 to 3.0) is about 1% per year.67,96,99The risk of major bleeding is expected to be at least 10-fold higher in patients with multiple risk factors for bleeding.97
 

Figure 5. Steps for Selecting Duration of Anticoagulation

Algorithm outlines the steps for selecting the duration of anticoagulation for patients with venous thromboembolism.

These findings permit the construction of an algorithm for selecting duration of anticoagulation for VTE [see Figure 5]. Whether anticoagulant therapy (INR of 2.0 to 3.0) is recommended for 3 months, 6 months, or an indefinite period (with annual review) depends primarily on the presence of a provoking risk factor for VTE (i.e., major or minor transient risk factor, no risk factor, or cancer), risk factors for bleeding, and patient preference (i.e., burden associated with treatment). Secondary considerations include such factors as whether the patient has had a previous unprovoked VTE, whether the VTE presented as DVT or as PE, and whether the patient has biochemical risk factors for recurrent VTE.

Venous Thromboembolism in Pregnancy

The management of VTE during pregnancy is complicated because clinical diagnosis is unreliable, some of the objective diagnostic tests are potentially harmful to the fetus, and treatment may cause teratogenicity or fetal bleeding.100,101

Diagnosis

In pregnant patients suspected of having DVT, venous ultrasonography of the proximal veins, including the iliac vein, should be used as the initial test.34,101 If the result is unequivocally abnormal, a diagnosis of DVT is made and the patient is treated with anticoagulants. If the test result is normal, either a limited venogram can be performed with abdominal shielding to exclude isolated calf vein thrombosis, or serial compression ultrasonography can be performed on two occasions over the next 14 days. MRI may also be considered if there is continuing concern about iliac vein thrombosis. D-dimer testing may also be used as previously described, although false positive results are more common with this test, particularly in late pregnancy.

The diagnostic approach to PE in pregnancy is similar to that used in nonpregnant patients, but with the following modifications. Ultrasonography of the proximal deep veins can be performed first. If DVT is present, the patient is started on anticoagulant therapy without the need for further diagnostic testing. If DVT is not diagnosed, lung scanning or CTPA can be performed, but the techniques should be modified to reduce exposure of the fetus to radiation.101

Treatment

The treatment of VTE is much more complicated in pregnant patients because oral anticoagulants cross the placenta and, if administered during the first trimester, can cause warfarin embryopathy, which is characterized by nasal hypoplasia and skeletal abnormalities.100Warfarin administered during the second and third trimesters can cause dorsal midline dysplasia, abnormalities of the ventricular system, and optic atrophy.

Heparin does not cross the placenta and is much safer than oral anticoagulants during pregnancy. Although there have been reports associating heparin therapy during pregnancy with a high incidence of stillbirth or prematurity, most of these complications occurred in mothers receiving heparin for disorders that are known to be associated with a high rate of fetal loss. Other studies have shown that heparin is safe for the fetus but, when used on a long-term basis during pregnancy, can produce osteoporosis in the mother. The incidence of heparin-induced osteopenia diagnosed by dual-photon absorption x-ray or by conventional x-ray may be as high as 30%, but overt fractures are uncommon, occurring in fewer than 5% of patients. Heparin-induced bleeding is not a common problem during pregnancy, provided that heparin therapy is monitored carefully. The anticoagulant response to heparin can be prolonged if the drug is administered in high doses just before parturition, so there is the potential for local bleeding during and immediately after delivery.

In pregnant patients with acute VTE, continuous intravenous heparin or twice-daily LMWH should be administered for 4 to 7 days. This is followed for the remainder of the pregnancy by subcutaneous heparin, adjusted to achieve aPTT values or heparin levels that are in the therapeutic range midway between injections, or by continued use of LMWH.89 An unwanted anticoagulant effect during delivery can be avoided by discontinuing subcutaneous heparin therapy 24 hours before elective induction of labor.

If there is no evidence of excessive postpartum bleeding, heparin therapy can be resumed within 12 hours of delivery and continued until oral anticoagulation is established. The intensity of heparin therapy will depend on the amount of time that has passed since the diagnosis of VTE was made: if the diagnosis was made less than 1 month ago, therapeutic doses may be used (with stepwise increases in subcutaneous or intravenous doses over 24 hours); if the diagnosis was made more than 1 month ago, prophylactic or intermediate doses of heparin may be used. Warfarin is started at the same time as heparin and is continued for a minimum of 6 weeks and preferably until patients have received a minimum of 3 months of anticoagulation. Warfarin does not enter breast milk and therefore can be administered to nursing mothers.87,88

Miscellaneous Thromboembolic Disorders

Thrombosis in Unusual Sites

Subclavian or Axillary Veins

Thrombosis of the subclavian or axillary veins may be idiopathic or may occur as a complication of local vascular damage.102 It is now most frequently seen as a complication of chronic indwelling catheter use, but it also occurs as a complication after mastectomy and local radiotherapy for breast cancer. Idiopathic subclavian or axillary vein thrombosis often occurs in young muscular individuals and may be preceded by repetitive, strenuous activity involving the affected arm. Some of these persons have a fixed stenosis of the subclavian vein that is thought to be caused by external compression of the vein as it courses behind the clavicle. Occasionally, subclavian or axillary vein thrombosis can occur in patients with congenital deficiency of antithrombin, protein C, or protein S or in patients with antiphospholipid antibodies. Thrombosis of the axillary or subclavian vein or the superior vena cava is a rare complication of an implantable perivenous endocardial pacing system.

Subclavian or axillary thrombosis causes pain, edema, and cyanosis of the arm. In rare cases, the thrombosis extends into the superior vena cava and causes edema and cyanosis of the face and neck. Definitive diagnosis is made by venography, venous ultrasonography, CT, or MRI.103 Subclavian or axillary vein thrombosis is usually treated with anticoagulants. Regional or systemic thrombolytic therapy may be considered in young patients without contraindications, because a substantial number of these patients experience aching and swelling when they exert the affected arm.

Mesenteric Vein

An uncommon disorder, mesenteric vein thrombosis usually occurs in the sixth or seventh decade of life. It generally involves segments of the small bowel, leading to hemorrhagic infarction.104,105 Affected patients often have associated disorders, such as inflammatory bowel disease, malignancy, portal hypertension, or familial thrombophilia or polycythemia vera, or they may have a history of recent abdominal surgery. In about 20% of cases, no underlying cause is found.

The clinical manifestations of mesenteric vein thrombosis include intermittent abdominal pain, abdominal distention, vomiting, diarrhea, and melena. Blunt, semiopaque indentations of the bowel lumen (“thumbprinting”) due to mucosal edema; gas in the wall of the bowel or the portal vein; or free peritoneal air may occur secondary to bowel infarction. CT, which shows an intraluminal filling defect in the mesenteric vein, is the diagnostic test of choice, and both Doppler ultrasonography and MRI are also helpful. Management includes acute and long-term anticoagulation, supportive care, and surgery if bowel resection is being considered. Mortality is about 30%, and up to 30% of patients experience a recurrence.

Renal Vein

Renal vein thrombosis can be idiopathic, or it may occur as a complication of the nephrotic syndrome. Patients may be asymptomatic or may present with abdominal, back, or flank pain and tenderness. PE is a relatively common complication of renal vein thrombosis. Anticoagulant therapy results in a gradual improvement in renal function, but patients may have long-standing proteinuria. Thrombolytic agents have been used, but the data are inadequate for critical appraisal of this form of treatment.

Thrombophilia

The term thrombophilia denotes any increased tendency to thrombosis, whether inherited or acquired.9,10 Thrombophilia is discussed in detail elsewhere [see 5:XIV Thrombotic Disorders].

References

  1. White RH: The epidemiology of venous thromboembolism. Circulation 107:I4,2003
  2. Anderson FA Jr, Spencer FA: Risk factors for venous thromboembolism. Circulation 107:I9,2003
  3. Heit JA, Silverstein MD, Mohr DN, et al: Risk factors for deep vein thrombosis and pulmonary embolism: a population-Based case-control study. Arch Intern Med 160:809,2000
  4. Anderson FA, Wheeler HB, Goldberg RJ, et al: The prevalence of risk factors for venous thromboembolism among hospital patients. Arch Intern Med 152:1660,1992
  5. Cogo A, Bernardi E, Prandoni P, et al: Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 154:164,1994
  6. Kearon C: Natural history of venous thromboembolism. Circulation 107:I22,2003
  7. Kahn SR, Ginsberg JS: Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med 164:17,2004
  8. Kearon C, Salzman E, Hirsh J: Epidemiology, pathogenesis, and natural history of venous thrombosis. Hemostasis and Thrombosis, 4thed. Colman R, Hirsh J, Marder JV, Eds. Lippincott Williams & Wilkins, Philadelphia, 2001
  9. Lane DA, Mannucci PM, Bauer KA, et al: Inherited thrombophilia: Part 1. Thromb Haemost 76:651,1996
  10. Lane DA, Mannucci PM, Bauer KA, et al: Inherited thrombophilia: Part 2. Thromb Haemost 76:824,1996
  11. Heijboer H, Brandjes PM, Buller HR, et al: Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 323:1512,1990
  12. Kearon C, Crowther M, Hirsh J: Management of patients with hereditary hypercoagulable disorders. Ann Rev Med 51:169,2000
  13. Kearon C, Gent M, Hirsh J, et al: A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 340:901,1999
  14. Poort SR, Rosendaal FR, Reitsma PH, et al: A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88:3698,1996
  15. Vandenbroucke JP, Koster T, Briet E, et al: Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V leiden mutation. Lancet 344:1453,1994
  16. Grady D, Herrington D, Bittner V, et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 288:49,2002
  17. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321,2002
  18. Hoibraaten E, Qvigstad E, Arnesen H, et al: Increased risk of recurrent venous thromboembolism during hormone replacement therapy—results of the randomized, double-Blind, placebo-controlled Estrogen in Venous Thromboembolism Trial (EVTET). Thromb Haemost 84:961,2000
  19. Hull R, Delmore T, Genton E, et al: Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 301:855,1979
  20. Lagerstedt CI, Olsson CG, Fagher BO, et al: Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 2:515,1985
  21. van Dongen CJJ, van der Belt AGM, Prins MH, et al: Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 4:CD001100,2004
  22. Baglin T, Luddington R, Brown K, et al: Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 362:523,2003
  23. Levine MN, Hirsh J, Gent M, et al: Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 74:606,1995
  24. Pinede L, Ninet J, Duhaut P, et al: Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 103:2453,2001
  25. Schulman S, Rhedin A-S, Lindmarker P, et al: A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 332:1661,1995
  26. Agnelli G, Prandoni P, Santamaria MG, et al: Three months versus one year of oral anticoagulant therapy for idiopathic deep vein thrombosis. N Engl J Med 345:165,2001
  27. Agnelli G, Prandoni P, Becattini C, et al: Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 139:19,2003
  28. Research Committee of the British Thoracic Society: Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 340:873,1992
  29. Lim W, Crowther A, Eikelboom JW: Management of antiphospholipid antibody syndrome: a systematic review. JAMA 295:1050,2006
  30. McRae S, Tran H, Schulman S, et al: Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 368:371,2006
  31. Ho WK, Hankey GJ, Quinlan DJ, et al: Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 166:729,2006
  32. Palareti G, Legnani C, Cosmi B, et al: Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 108:313,2003
  33. Christiansen SC, Cannegieter SC, Koster T, et al: Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 293:2352,2005
  34. Kearon C, Julian A, Newman TE, Ginsberg JS, for the McMaster Diagnostic Imaging Practice Guidelines Initiative: Non-invasive diagnosis of deep vein thrombosis. Ann Intern Med 128:663,1998
  35. Wells PS, Owen C, Doucette S, Fergusson D, Tran H: Does this patient have deep vein thrombosis? JAMA 295:199,2006
  36. Stein PD, Hull RD, Patel KC, et al: D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 140:589,2004
  37. Kelly J, Rudd A, Lewis RR, Hunt BJ: Plasma D-dimers in the diagnosis of venous thromboembolism. Arch Intern Med 162:747,2002
  38. Perrier A, Desmarais S, Miron MJ, et al: Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 353:190,1999
  39. Wells PS, Anderson DR, Rodger M, et al: Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 349:1227,2003
  40. Kearon C, Ginsberg JS, Douketis J, et al: A randomized trial of diagnostic strategies after normal proximal vein ultrasonography for suspected deep venous thrombosis: D-dimer testing compared with repeated ultrasonography. Ann Intern Med 142:490,2005
  41. Rathbun SW, Whitsett TL, Raskob GE: Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial. Ann Intern Med 141:839,2004
  42. Linkins L, Pasquale P, Paterson S, et al: Change in thrombus length on venous ultrasound and recurrent deep vein thrombosis. Arch Intern Med 164:1793,2004
  43. Kearon C: Diagnosis of pulmonary embolism. CMAJ 168:183,2003
  44. Simonneau G, Sors H, Charbonnier B, et al: A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 337:663,1997
  45. Chunilal SD, Eikelboom JW, Attia J, et al: Does this patient have pulmonary embolism? JAMA 290:2849,2003
  46. Le Gal G, Righini M, Roy PM, et al: Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 144:165,2006
  47. Wells PS, Anderson DR, Rodger M, et al: Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 83:416,2000
  48. Kearon C, Ginsberg JS, Douketis J, et al: An evaluation of D-dimer in the diagnosis of pulmonary embolism: a randomized trial. Ann Intern Med 144:812,2006
  49. van Belle A, Buller HR, Huisman MV, et al: Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 295:172,2006
  50. Stein PD, Fowler SE, Goodman LR, et al: Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 354:2317,2006
  51. Quiroz R, Kucher N, Zou KH, et al: Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systematic review. JAMA 293:2012,2005
  52. Roy PM, Colombet I, Durieux P, et al: Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. Br Med J 331:259,2005
  53. Kruip MJ, Leclercq MG, van der HC, et al: Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies: A systematic review. Ann Intern Med 138:941,2003
  54. Wells PS, Ginsberg JS, Anderson DR, et al: Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 129:997,1998
  55. Hirsh J, Raschke R: Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:188S,2004
  56. Kearon C, Ginsberg JS, Julian JA, et al: Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute venous thromboembolism. JAMA 296:935,2006
  57. Quinlan DJ, McQuillan A, Eikelboom JW: Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med 140:175,2004
  58. Lee AY, Levine N, Baker RI, et al: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146,2003
  59. Buller HR, Agnelli G, Hull RD, et al: Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:401S,2004
  60. Weitz JI, Hirsh J, Samama MM: New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:265S,2004
  61. Turpie AG, Bauer KA, Eriksson BI, et al: Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-Blind studies. Arch Intern Med 162:1833,2002
  62. Buller HR, Davidson BL, Decousus H, et al: Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 349:1695,2003
  63. Buller HR, Davidson BL, Decousus H, et al: Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 140:867,2004
  64. Ansell J, Hirsh J, Poller L, et al: The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:204S,2004
  65. Fiessinger JN, Huisman MV, Davidson BL, et al: Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 293:681,2005
  66. Levine MN, Raskob G, Beyth RJ, et al: Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:287S,2004
  67. Kearon C, Ginsberg JS, Kovacs MJ, et al: Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 349:631,2003
  68. Geerts WH, Pineo GF, Heit JA, et al: Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:338S,2004
  69. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial [see comments]. Lancet 355:1295,2000
  70. Eikelboom JW, Quinlan J, Douketis JD: Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 358:9,2001
  71. Decousus H, Leizorovicz A, Parent F, et al: A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 338:409,1998
  72. Fedullo PF, Auger WR, Kerr KM, et al: Chronic thromboembolic pulmonary hypertension. N Engl J Med 345:1465,2001
  73. Brandjes DPM, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al: Randomised trial of effect of compress stockings in patients with syptomatic proximal-vein thrombosis. Lancet 349:759,1997
  74. Prandoni P, Lensing AW, Prins MH, et al: Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 141:249,2004
  75. Ridker PM, Goldhaber SZ, Danielson E, et al: Long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism. N Engl J Med 348:1425,2003
  76. Kearon C, Ginsberg JS, Anderson DR, et al: Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost 2:743,2004
  77. Prandoni P, Lensing AWA, Cogo A, et al: The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 125:1,1996
  78. Pini M, Aiello S, Manotti C, et al: Low molecular weight heparin versus warfarin for the prevention of recurrence after deep vein thrombosis. Thromb Haemost 72:191,1994
  79. Pinede L, Duhaut P, Cucherat M, et al: Comparison of long versus short duration of anticoagulant therapy after a first episode of venous thromboembolism: a meta-analysis of randomized, controlled trials. J Intern Med 247:553,2000
  80. Lindmarker P, Schulman S: The risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg: The DURAC Trial Study Group. J Intern Med 247:601,2000
  81. Schulman S, Granqvist S, Holmstrom M, P, et al: The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 336:393,1997
  82. Murin S, Romano S, White RH: Comparison of outcomes after hospitalization for deep vein thrombosis or pulmonary embolism. Thromb Haemost 88:407,2002
  83. Schulman S, Svenungsson E, Granqvist S: Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 104:332,1998
  84. Schulman S, Wahlander K, Lundström T, Clason SB, Eriksson H, for the THRIVE III Investigators: Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 349:1713,2003
  85. Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS: Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 279:458,1998
  86. Heit JA, Mohr DN, Silverstein MD, et al: Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-Based cohort study. Arch Intern Med 160:761,2000
  87. Kniffin WD Jr, Baron JA, Barrett J, et al: The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 154:861,1994
  88. Schulman S, Lindmarker P, Holmstrom M, et al: Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 4:724,2006
  89. Kearon C: Duration of therapy for acute venous thromboembolism. Clin Chest Med 24:63,2003
  90. Palareti G, Legnani C, Cosmi B, et al: Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 87:7,2002
  91. Lee AYY, Levine MN, Baker RI, et al: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146,2003
  92. Grady D, Wenger NK, Herrington D, et al: Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med 132:689,2000
  93. Lindmarker P, Schulman S, Sten-Linder M, et al: The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. Thromb Haemost 81:684,1999
  94. Eichinger S, Pabinger I, Stumpflen A, et al: The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 77:624,1997
  95. Kearon C: Long-term management of patients after venous thromboembolism. Circulation 110 (suppl I):I10,2004
  96. Levine MN, Raskob G, Landefeld S, et al: Hemorrhagic complications of anticoagulant treatment. Chest 119:108S,2001
  97. Beyth RJ, Quinn M, Landefeld S: Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 105:91,1998
  98. Linkins L, Choi T, Douketis JD: Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 139:893,2003
  99. Ansell J, Hirsh J, Dalen J, et al: Managing oral anticoagulant therapy. Chest 119:22S,2001
  100. Bates SM, Greer IA, Hirsh J, et al: Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:627S,2004
  101. Bates SM, Ginsberg JS: How we manage venous thromboembolism during pregnancy. Blood 100:3470,2002
  102. Baarslag HJ, van Beek EJ, Koopman MM, et al: Prospective study of color duplex ultrasonography compared with contrast venography in patients suspected of having deep venous thrombosis of the upper extremities. Ann Intern Med 136:865,2002
  103. Kumar S, Sarr G, Kamath PS: Mesenteric venous thrombosis. N Engl J Med 345:1683,2001
  104. Oldenburg WA, Lau LL, Rodenberg TJ, et al: Acute mesenteric ischemia: a clinical review. Arch Intern Med 164:1054,2004
  105. Holbrook AM, Pereira JA, Labiris R, et al: Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165:1095,2005

Editors: Dale, David C.; Federman, Daniel D.