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CHAPTER 129 VENOUS THROMBOSIS

CHAPTER 129 VENOUS THROMBOSIS
Williams Hematology

CHAPTER 129 VENOUS THROMBOSIS

GARY E. RASKOB
RUSSELL D. HULL
GRAHAM F. PINEO

Definition and History
Etiology and Pathogenesis
Clinical Features
Laboratory Features
Differential Diagnosis

Differential Diagnosis of Deep-Vein Thrombosis

Objective Testing for Deep-Vein Thrombosis

Differential Diagnosis of Pulmonary Embolism

Objective Testing for Pulmonary Embolism
Therapy, Course, and Prognosis

Clinical Course of Venous Thromboembolism

Objectives of Antithrombotic Treatment

Anticoagulant Therapy

Thrombolytic Therapy

Inferior Vena Cava Filter
Chapter References

This chapter provides an overview of the diagnosis and treatment of venous thrombosis, and its major complication, pulmonary embolism. Clinical recommendations are linked to the strength of the evidence from clinical trials. Most clinically important pulmonary emboli arise from proximal deep-vein thrombosis (thrombosis involving the popliteal, femoral, or iliac veins). Upper-extremity deep-vein thrombosis may also lead to clinically important pulmonary embolism. The clinical features of both deep-vein thrombosis and pulmonary embolism are nonspecific, and objective testing is required to confirm or exclude the presence of venous thromboembolism. Strategies for the diagnosis of venous thromboembolism include tests for the detection of pulmonary embolism (lung scanning or pulmonary angiography) and tests for deep-vein thrombosis of the legs (ultrasound, impedance plethysmography, or venography). The measurement of plasma D-dimer by a rapid ELISA technique is useful as an exclusion test in patients with clinically suspected venous thromboembolism. Spiral CT or magnetic resonance imaging (MRI) are useful tests for ruling in the diagnosis of pulmonary embolism if positive results are obtained, but the safety of withholding treatment in patients with negative results remains uncertain. Anticoagulant treatment with continuous intravenous heparin or subcutaneous low-molecular-weight heparin, followed by long-term treatment with oral warfarin sodium, is the treatment of choice for most patients with proximal deep-vein thrombosis and/or submassive pulmonary embolism. Low-molecular-weight heparin enables outpatient therapy for many patients with uncomplicated venous thromboembolism. Thrombolytic therapy is indicated for patients with pulmonary embolism who present with cardiovascular collapse or who have clinical or echocardiographic findings of right ventricular impairment. The role of thrombolytic therapy for patients with deep-vein thrombosis is limited because it remains uncertain whether systemic or catheter-directed thrombolysis will reduce the incidence of the postphlebitic syndrome. The insertion of a vena cava filter is effective for preventing major pulmonary embolism and is indicated for patients with acute venous thromboembolism who have an absolute contraindication to anticoagulant therapy or who have recurrent venous thromboembolism despite adequate anticoagulant treatment.

Acronyms and abbreviations that appear in this chapter include: APTT, activated partial thromboplastin time; DVT, deep-vein thrombosis; ELISA, enzyme-linked immunosorbent assay; HIT, heparin-induced thrombocytopenia; IPG, impedance plethysmography; LMW, low-molecular-weight; MRI, magnetic resonance imaging; PE, pulmonary embolism.

DEFINITION AND HISTORY
Venous thrombosis commonly develops in the deep veins of the leg or the arm, or in the superficial veins of these extremities. Superficial venous thrombosis is a relatively benign disorder unless extension into the deep venous system develops. Thrombosis involving the deep veins of the leg is divided into two prognostic categories: (1) calf-vein thrombosis in which thrombi remain confined to the deep calf veins, and (2) proximal-vein thrombosis in which thrombosis involves the popliteal, femoral, or iliac veins (see “Therapy, Course, and Prognosis,” below).1
Pulmonary emboli originate from thrombi in the deep veins of the leg in 90 percent or more of patients. Other less common sources of pulmonary embolism include the deep pelvic veins, renal veins, inferior vena cava, right side of the heart, or the axillary veins. Most clinically important pulmonary emboli arise from proximal deep-vein thrombosis of the leg. Upper-extremity deep-vein thrombosis may also lead to clinically important pulmonary embolism.2 Deep-vein thrombosis and/or pulmonary embolism are referred to collectively as venous thromboembolism.
Venous thromboembolism is a common disorder. The estimated annual incidence of symptomatic venous thromboembolism is 117 cases per 100,000 population.3 This translates to more than 250,000 patients each year in the United States. The incidence of venous thromboembolism increases with each decade over the age of 60. The large proportion of the United States’ population that will soon enter into the older age group will make venous thromboembolism an increasingly important national health problem.3
Effective prophylaxis against venous thromboembolism is now available for most high-risk patients. The use of prophylaxis is more effective for preventing death and morbidity from venous thromboembolism than is treatment of the established disease. Evidence-based recommendations for the prevention of venous thromboembolism have been published recently.4
Historically, venous thromboembolism usually occurred in sick hospitalized patients. More recently, the burden of illness from venous thromboembolism has shifted to the community setting such that most patients now present as outpatients to their primary care physician or the emergency room. The reason for this shift has been the greatly reduced lengths of hospital stay for most surgical procedures or medical conditions in recent years. Consequently, patients who are placed at risk for venous thromboembolism because of surgery or medical illness are discharged from the hospital either before the period of risk has ended or with subclinical venous thrombi present that subsequently evolve and lead to symptomatic deep-vein thrombosis or pulmonary embolism. The shift in burden of illness from the hospital to community setting has stimulated the development of effective, safe, and cost-effective methods for outpatient diagnosis and management.
ETIOLOGY AND PATHOGENESIS
Venous thrombi are composed mainly of fibrin and red blood cells, with variable platelet and leukocyte components. The formation, growth, and breakdown of venous thromboemboli reflect a balance between thrombogenic stimuli and protective mechanisms. The thrombogenic stimuli are (1) venous stasis, (2) activation of blood coagulation, and (3) vein damage. The protective mechanisms are (1) the inactivation of activated coagulation factors by circulating inhibitors (e.g., antithrombin III, activated protein C), (2) clearance of activated coagulation factors and soluble fibrin polymer complexes by the reticuloendothelial system and by the liver, and (3) lysis of fibrin by fibrinolytic enzymes derived from plasma, endothelial cells, and leukocytes.
Risk factors for venous thromboembolism include advancing age (greater than 40 years), a past history of venous thromboembolism, surgery or trauma, immobilization, cancer, congestive heart failure, myocardial infarction, leg paralysis, estrogens, pregnancy or postpartum state, varicose veins, obesity, antiphospholipid antibody syndrome, hyperhomocysteinemia, and several inherited prothrombotic conditions. These inherited conditions include activated protein C resistance, prothrombin 20210 A, deficiencies of antithrombin III, protein C or protein S, and several types of dysfibrinogenemia (see Chap. 124 and Chap. 127). The risk of thromboembolism is increased when more than one predisposing factor is present.
Activated protein C resistance is the most common hereditary abnormality predisposing to venous thrombosis. The defect is due to substitution of glutamine for arginine at residue 506 in the factor V molecule, making factor V resistant to proteolysis by activated protein C. The gene mutation is commonly designated as factor V Leiden and follows autosomal dominant inheritance. Patients who are homozygous for the factor V Leiden mutation have a markedly increased risk of thromboembolism and present with clinical thromboembolism at a younger age (median 31 years) than those who are heterozygous (median age 46 years).5 Factor V Leiden is present in approximately 5 percent of the normal Caucasian population, in 16 percent of patients with a first-episode of deep-vein thrombosis, and in up to 35 percent of patients with idiopathic deep-vein thrombosis.6 Prothrombin 20210 A is a recently identified gene mutation predisposing to venous thromboembolism. It is present in approximately 2 to 3 percent of apparently healthy individuals and in 7 percent of those with deep-vein thrombosis.7 In 40 percent to up to 60 percent of patients with idiopathic deep-vein thrombosis, an inherited abnormality cannot be detected, suggesting that other gene mutations are present and may have an etiologic role.
Pulmonary embolism occurs in 50 percent of patients with objectively documented proximal-vein thrombosis.1 Many of these emboli are asymptomatic. The clinical importance of pulmonary embolism depends on the size of the embolus and the patient’s cardiorespiratory reserve. Usually only part of the thrombus embolizes, and thus 30 percent to 70 percent of patients with pulmonary embolism by angiography also have detectable deep-vein thrombosis of the legs.8 Deep-vein thrombosis and pulmonary embolism are not separate disorders but a continuous syndrome of venous thromboembolism, in which the initial clinical presentation may be symptoms of either deep-vein thrombosis or pulmonary embolism. Strategies for the detection of venous thromboembolism include tests for the detection of pulmonary embolism (lung scanning or pulmonary angiography)8,9 and tests for deep-vein thrombosis of the legs (ultrasound, impedance plethysmography, or venography)10,11 and 12 (see sections on “Objective Testing”).
CLINICAL FEATURES
The clinical features of venous thrombosis include leg pain, tenderness, and swelling, a palpable cord (i.e., a thrombosed vessel that is palpable as a cord), discoloration, venous distention, and prominence of the superficial veins, and cyanosis. The clinical diagnosis of deep-vein thrombosis is highly nonspecific because each of the symptoms or signs may be caused by nonthrombotic disorders. The rare exception is the patient with phlegmasia cerulea dolens, in whom the diagnosis of massive ilieofemoral thrombosis is obvious. This syndrome occurs in less than 1 percent of patients with symptomatic venous thrombosis. In most patients, the symptoms and signs are nonspecific, and in 50 percent to 85 percent of patients the clinical suspicion of deep-vein thrombosis is not confirmed by objective testing.10,11 and 12 Patients with minor symptoms and signs may have extensive deep-venous thrombi. Conversely, patients with florid leg pain and swelling, suggesting extensive deep-vein thrombosis, may have negative results by objective testing. Patients can be assigned pretest probabilities of deep-vein thrombosis based on the patient’s clinical features and history. However, these pretest probabilities are neither sufficiently high to give anticoagulant treatment or sufficiently low to withhold treatment without performing objective testing.
The clinical features of acute pulmonary embolism include the following syndromes which may overlap: (1) transient dyspnea and tachypnea in the absence of other clinical features, (2) the syndrome of pulmonary infarction or congestive atelectasis (also known as ischemic pneumonitis or incomplete infarction), including pleuritic chest pain, cough, hemoptysis, pleural effusion, and pulmonary infiltrates on chest radiograph, (3) right-sided heart failure associated with severe dyspnea and tachypnea, (4) cardiovascular collapse with hypotension, syncope, and coma (usually associated with massive pulmonary embolism), and (5) several less common and nonspecific clinical presentations including unexplained tachycardia or arrhythmia, resistant cardiac failure, wheezing, cough, fever, anxiety/apprehension, or confusion. All the above clinical features are nonspecific and may be caused by a variety of cardiorespiratory disorders. Objective testing is mandatory to confirm or exclude the presence of pulmonary embolism. Classifying patients into categories of pretest probability (low, intermediate, or high) is useful in only a minority of patients when combined with lung scan findings.
LABORATORY FEATURES
Venous thromboembolism is associated with nonspecific laboratory changes that make up the acute-phase response to tissue injury. This response includes elevated levels of fibrinogen and factor VIII, increases in the leukocyte and platelet counts, and systemic activation of blood coagulation, fibrin formation, and fibrin breakdown, with increases in the plasma concentrations of prothrombin fragment 1.2, fibrinopeptide A, complexes of thrombin-antithrombin III, and fibrin degradation products. All these changes are nonspecific and may occur as the result of surgery, trauma, infection, inflammation, or infarction. None of the reported laboratory changes can be used to predict the development of venous thromboembolism.
The fibrin breakdown fragment D-dimer can be measured by an enzyme-linked immunosorbant assay or by a latex agglutination assay. Some of these assays have a rapid turnaround time and some are quantitative. The D-dimer may be useful as an exclusionary test for patients with suspected venous thromboembolism (see sections on “Objective Testing”).13,14,15 and 16 A positive result is highly nonspecific.13,14
DIFFERENTIAL DIAGNOSIS
DIFFERENTIAL DIAGNOSIS OF DEEP-VEIN THROMBOSIS
The differential diagnosis in patients with clinically suspected deep-vein thrombosis includes muscle strain or tear, direct twisting injury to the leg, lymphangitis or lymphatic obstruction, venous reflux, popliteal cyst, cellulitis, leg swelling in a paralyzed limb, and abnormality of the knee joint. An alternate diagnosis is frequently not evident at presentation, and so, without objective testing, it is impossible to exclude deep-vein thrombosis. The cause of symptoms can often be determined by careful follow-up once deep-vein thrombosis has been excluded by objective testing. In approximately 25 percent of patients, however, the cause of pain, tenderness, and swelling remains uncertain even after careful follow-up.
OBJECTIVE TESTING FOR DEEP-VEIN THROMBOSIS
The objective tests that have a role in diagnosing patients with clinically suspected deep-vein thrombosis are ultrasound imaging, impedance plethysmography, and venography. Each of these tests has been validated by properly designed clinical trials, including prospective studies with long-term follow-up that have established the safety of withholding anticoagulant treatment in patients with negative test results.10,11,17
Noninvasive testing with either ultrasound imaging or impedance plethysmography is effective for identifying patients with proximal-vein thrombosis. Both tests have limited sensitivity for calf-vein thrombosis and require serial testing to detect extension of calf-vein thrombosis into the popliteal vein or more proximally. When performed serially, these tests can safely replace venography in symptomatic patients. Venography continues to have an important role in selected patients, such as those for whom serial testing is impractical, and those with abnormal noninvasive test results who have conditions known to produce false positive results.
The wide availability of ultrasound imaging has supplanted impedance plethysmography as the principal noninvasive test for deep-vein thrombosis in most centers. However, the value of impedance plethysmography for patients with suspected acute recurrent deep-vein thrombosis is underappreciated. One logical approach is to use ultrasound imaging with vein compression as the initial test for patients with suspected first-episode deep-vein thrombosis (Fig. 129-1) and impedance plethysmography as the preferred initial test for patients with suspected recurrent deep-vein thrombosis (Fig. 129-2).

FIGURE 129-1 Diagnosis and therapy of patients with suspected first-episode deep-vein thrombosis (DVT). Imaging of the common femoral vein in the groin and of the popliteal vein in the popliteal fossa extending distally 10 cm from mid-patella.
*Repeat test can be avoided if a measurement of plasma D-dimer is negative using a rapid ELISA technique.15
†Perform additional testing, including venography and/or CT or MR imaging, if ultrasound is abnormal only at the common femoral vein site.

FIGURE 129-2 Diagnosis and therapy of patients with suspected recurrent deep-vein thrombosis.
*Venography should also be performed in patients with new abnormal IPG results if a concurrent condition is present that can produce falsely abnormal test results.
†The criterion for diagnosing an acute recurrent deep-vein thrombosis by venography is the finding of a new intraluminal filling defect that is constant on all films. In some patients, venography cannot establish or exclude the presence of acute recurrent deep-vein thrombosis (i.e. an indeterminate venogram), due to the presence of persistent intraluminal filling defects, non-visualized venous segments, and/or extensive collateral veins. In such patients, anticoagulant treatment should probably be given rather than risk death from massive pulmonary embolism.

Ultrasound imaging using vein compression has two practical advantages: (1) It is more sensitive than impedance plethysmography for small nonocclusive thrombi that barely extend into the popliteal vein, and this enables serial testing to be limited to a single repeat test done 5 to 7 days after presentation, and (2) it is not influenced by congestive cardiac failure or by disorders which impair deep-venous filling (e.g., peripheral arterial disease), which may produce false positive impedance plethysmography results. In the absence of these conditions, impedance plethysmography has a similarly high positive predictive value (>90%) to compression ultrasound,10,11 but clinical examination of the patient is required to exclude potential causes of false positive results.
Impedance plethysmography is a valuable test for patients with suspected recurrent deep-vein thrombosis because the test returns to normal earlier in patients with proximal-vein thrombosis than does compression ultrasound. Impedance plethysmography returns to normal in 65 percent of patients by 3 months, 85 percent by 6 months, and 95 percent by 1 year, compared to 30 percent, 45 percent, and 60 percent respectively for compression ultrasound. Compression ultrasound may remain abnormal for 2 years or more due to persistent noncompressibility of the vein caused by fibrous organization of the original thrombus. A normal impedance plethysmography result obtained at the time of completing anticoagulant treatment at 3 to 6 months provides a useful baseline for future comparison. An impedance plethysmography result which has changed from normal to abnormal is highly predictive of acute recurrent proximal-vein thrombosis.12 The finding of a new noncompressible venous segment by ultrasound is probably highly predictive of acute recurrent thrombosis, but this criterion is of limited value, since many patients have persistently noncompressible venous segments due to the initial episode. To date, no criteria by ultrasound imaging for the presence or absence of acute recurrent deep-vein thrombosis have been validated by prospective follow-up studies to establish the safety of withholding anticoagulant treatment.
Studies have suggested a high negative predictive value of D-dimer for acute deep-vein thrombosis.13,14,15 and 16 The measurement of plasma D-dimer is useful in patients with initially negative noninvasive test results to exclude the presence of deep-vein thrombosis and avoid the need for repeated testing.15 However, this is less important now in patients with suspected first-episode deep-vein thrombosis because the need for repeated testing with compression ultrasound has been reduced to a single repeat test at 5 to 7 days.10 Most patients require a follow-up clinic visit to determine the alternate diagnosis and guide for further care, so the return visit at 5 to 7 days has added practical value and is not a major inconvenience for most patients. Nevertheless, measurement of plasma D-dimer using a rapid semi-quantitative ELISA method avoids the need for repeat testing with compression ultrasound in most patients (87%).15 Initial promising results indicate that the rapid ELISA D-dimer test may replace ultrasound testing altogether in up to 30 percent of patients with suspected deep-vein thrombosis.16 However, further prospective studies in larger numbers of patients should be completed before the use of D-dimer testing alone is recommended.
The different D-dimer assays (latex agglutination, ELISA, or whole blood agglutination) have different sensitivities and specificities for deep-vein thrombosis. The clinical outcomes observed using one method may not be generalizeable to another. The decision to use the D-dimer test for patient care decisions depends on the local availability of an appropriate assay that has been validated by clinical outcome studies.
The value of D-dimer is potentially greater in patients with suspected acute recurrent deep-vein thrombosis. However, the safety of withholding anticoagulant treatment in such patients with negative D-dimer results has not been established by adequately designed clinical trials.
DIFFERENTIAL DIAGNOSIS OF PULMONARY EMBOLISM
The differential diagnosis in patients with suspected pulmonary embolism includes multiple cardiopulmonary disorders for each of the clinical syndromes. For the presentation of dyspnea and tachypnea these include atelectasis, pneumonia, pneumothorax, acute pulmonary edema, bronchitis, bronchiolitis, and acute bronchial obstruction. For the syndrome of pulmonary infarction (e.g., pleuritic chest pain, hemoptysis) these include pneumonia, pneumothorax, pericarditis, pulmonary or bronchial neoplasm, bronchiectasis, acute bronchitis, tuberculosis, diaphragmatic inflammation, myositis, muscle strain, and rib fracture. For the clinical presentation of right-sided heart failure, these include myocardial infarction, myocarditis, and cardiac tamponade. For cardiovascular collapse this includes myocardial infarction, acute massive hemorrhage, gram-negative septicemia, cardiac tamponade, and spontaneous pneumothorax.
OBJECTIVE TESTING FOR PULMONARY EMBOLISM
The key tests include lung scanning, pulmonary angiography, and objective testing for proximal deep-vein thrombosis. The diagnostic approach is summarized in Fig. 129-3.

FIGURE 129-3 Diagnosis and therapy of patients with suspected pulmonary embolism (PE).
*Nondiagnostic includes the intermediate, indeterminate, and low-probability lung scan patterns.
†Cardiorespiratory reserve is “inadequate” if one or more of the following are present: syncope, hypotension (systolic blood pressure less than 90 mm Hg), pulmonary edema, clinical findings of right heart failure or echocardiographic evidence of right ventricular hypokinesis, acute tachyarrhythmia, severe hypoxemia (PO2 < 50 mm Hg), or severe respiratory insufficiency (PCO2 < 45 mm Hg, FEV1 < 1.0, vital capacity < 1.5 liter).
‡CT or MR imaging may be performed before pulmonary angiography—a positive result by these imaging techniques is useful for establishing the presence of pulmonary embolism, but the safety of withholding treatment in patients with negative results by CT or MR imaging is uncertain (particularly in patients with inadequate cardiorespiratory reserve).

Objective testing for deep-vein thrombosis is useful in patients with suspected pulmonary embolism, particularly those with nondiagnostic lung scan results (indeterminate, intermediate, or low-probability categories). The detection of proximal-vein thrombosis by objective testing provides an indication for anticoagulant treatment, regardless of the presence or absence of pulmonary embolism, and avoids the need for further testing. A negative result by objective testing for deep-vein thrombosis does not exclude the presence of pulmonary embolism.8 If the patient has adequate cardiorespiratory reserve, then serial noninvasive testing for proximal-vein thrombosis may be used as an alternative to pulmonary angiography18 (see Fig. 129-3). The rationale is that the clinical objective in such patients is to prevent recurrent pulmonary embolism, which is unlikely in the absence of proximal-vein thrombosis. For patients with inadequate cardiorespiratory reserve (Fig. 129-3), the clinical objective is to prevent death and morbidity from an existing embolus, and further testing for the presence or absence of pulmonary embolism is needed.
Both spiral CT imaging and MRI are promising approaches for the diagnosis of pulmonary embolism.19,20 Spiral CT imaging is highly sensitive for large emboli (segmental or greater arteries) but is less sensitive for emboli in subsegmental pulmonary arteries. Such emboli may be clinically important in patients with inadequate cardiorespiratory reserve. MRI appears to be highly sensitive for pulmonary embolism. However, a recent study documented significant interobserver variation in the sensitivity, ranging from 70 percent to 100 percent.20 The safety of withholding anticoagulant treatment in patients with negative results by spiral CT imaging or MRI has not been established by prospective clinical trials incorporating long-term follow-up. Therefore, spiral CT or MRI are useful tests for ruling in the diagnosis of pulmonary embolism if positive results are obtained, but the validity of negative results remains uncertain.
The assay for plasma D-dimer is potentially useful to exclude pulmonary embolism based on a high negative predictive value reported in initial studies from centers with research expertise in measuring D-dimer.13,14 Promising outcome results have been obtained using a rapid ELISA technique.16 However, further studies in larger numbers of patients are required to establish the safety of withholding anticoagulant treatment in patients with suspected pulmonary embolism who have a negative D-dimer result.
THERAPY, COURSE, AND PROGNOSIS
CLINICAL COURSE OF VENOUS THROMBOEMBOLISM
Proximal deep-vein thrombosis is a serious and potentially lethal condition. Untreated proximal-vein thrombosis is associated with a 10 percent rate of fatal pulmonary embolism. Inadequately treated proximal-vein thrombosis results in a 20 percent to 50 percent risk of important recurrent venous thromboembolic events.21,22 and 23 Prospective studies of patients with clinically suspected deep-vein thrombosis or pulmonary embolism indicate that new venous thromboembolic events on follow-up are rare (£2%) among patients in whom proximal-vein thrombosis is absent by objective testing.10,11,15,16,17 and 18 The aggregate data from diagnostic and treatment studies indicate that the presence of proximal-vein thrombosis is the key prognostic marker for recurrent venous thromboembolism.
Thrombosis that remains confined to the calf-veins is associated with low risk (1 percent or less) of clinically important pulmonary embolism. Extension of thrombosis into the popliteal vein or more proximally occurs in 15 percent to 25 percent of patients with untreated calf-vein thrombosis.1 Patients with documented calf-vein thrombosis should either receive anticoagulant treatment to prevent extension or undergo monitoring for proximal extension using serial noninvasive tests.
Postphlebitic symptoms are common sequelae in patients with symptomatic proximal-vein thrombosis. A prospective study documented a 25 percent incidence of moderate to severe postphlebitic symptoms 2 years after the initial diagnosis of proximal-vein thrombosis in patients who were treated with initial heparin and oral anticoagulants for 3 months.24 This study also demonstrated that ipsilateral recurrent venous thrombosis is strongly associated with the subsequent development of moderate or severe postphlebitic symptoms.
OBJECTIVES OF ANTITHROMBOTIC TREATMENT
The objectives of treatment in patients with established venous thromboembolism are (1) to prevent death from pulmonary embolism, (2) to prevent morbidity from recurrent venous thrombosis or pulmonary embolism, and (3) to prevent or minimize the postphlebitic syndrome.
For most patients, the first two objectives are achieved by providing adequate anticoagulant treatment. Thrombolytic therapy is indicated in selected patients with pulmonary embolism (see “Thrombolytic Therapy”). The use of an inferior vena cava filter is indicated to prevent death from pulmonary embolism in patients in whom anticoagulant treatment is absolutely contraindicated and in other selected patients (see Inferior “Vena Cava Filter”).
ANTICOAGULANT THERAPY
Anticoagulant therapy is the treatment of choice for most patients with proximal-vein thrombosis or pulmonary embolism. The absolute contraindications to anticoagulant treatment include intracranial bleeding, serious active bleeding, recent brain, eye, or spinal cord surgery, and malignant hypertension. Relative contraindications include recent major surgery, recent cerebrovascular accident, active gastrointestinal tract bleeding, severe hypertension, severe renal or hepatic failure, and severe thrombocytopenia (platelets < 50,000/µl).
Patients with proximal-vein thrombosis require both adequate initial anticoagulant treatment with heparin or low-molecular-weight (LMW) heparin, and adequate long-term anticoagulant therapy to prevent recurrent venous thromboembolism.21,22 and 23 Adequate anticoagulant treatment reduces the incidence of recurrent venous thromboembolism during the first three months after diagnosis from 25 percent to 5 percent or less.21,22 and 23
Initial therapy with continuous intravenous heparin has been the standard approach for treatment of deep-vein thrombosis or pulmonary embolism for more than 20 years. More recently, LMW heparin given by subcutaneous injection once or twice daily has been shown to be as effective and safe as continuous intravenous heparin for the initial treatment of patients with proximal-vein thrombosis and submassive pulmonary embolism.21 If unfractionated heparin is given for initial therapy, it is important to achieve an adequate anticoagulant effect, defined as an activated partial thromboplastin time (APTT) above the lower limit of therapeutic range within the first 24 hours.22 Failure to achieve an adequate APTT effect early during therapy is associated with a high incidence (25%) of recurrent venous thromboembolism22; two-thirds of these recurrent events occur between 2 and 12 weeks after the initial diagnosis, despite treatment with oral anticoagulants.23 The clinical trial data indicate that the initial management with either unfractionated heparin or LMW heparin is critical to the patient’s long-term outcome.23
LMW heparin has the advantage that it does not require anticoagulant monitoring and dose finding. LMW heparin enables outpatient therapy for many patients with uncomplicated proximal-vein thrombosis. Outpatient LMW heparin therapy provides the potential for major cost savings to the health care system compared to therapy with unfractionated heparin in-hospital, without detracting from the effectiveness or safety of treatment. Further details of therapy with unfractionated heparin and LMW heparin are given in Chap. 133, including treatment regimens, monitoring, and adverse effects.
Oral anticoagulant therapy is begun together with initial heparin or LMW heparin therapy and overlapped for 4 to 5 days. Oral anticoagulant treatment is continued for 3 to 6 months in patients with a first-episode of proximal-vein thrombosis or pulmonary embolism. Stopping oral anticoagulant treatment at 4 to 6 weeks results in a high incidence (12% to 20%) of recurrent venous thromboembolism during the following 12 to 24 months.25 Oral anticoagulant treatment should be continued for 1 year to indefinitely in patients with a second episode of objectively documented venous thromboembolism.26 Stopping treatment at 3 months in these patients results in a 20 percent incidence of recurrent venous thromboembolism during the following year12,26 and a 5 percent incidence of fatal pulmonary embolism.12
The optimal duration of oral anticoagulant treatment for different patient subgroups is the subject of ongoing investigation. Long-term follow-up studies indicate that patients with a first episode of proximal-vein thrombosis who receive treatment for 3 months have a 25 percent incidence of recurrent venous thromboembolism during the subsequent 5 years.24 The patients at high risk of recurrent thromboembolism are those with idiopathic thrombosis and those with cancer.24 Conflicting data have been reported for the risk of recurrent venous thromboembolism among patients with the factor V Leiden mutation.6,27 Patients with advanced cancer remain at continued risk, and treatment should be continued indefinitely in these patients. Patients with idiopathic deep-vein thrombosis should be treated for at least 6 months.21 Treatment beyond 6 months for patients with a first-episode of either idiopathic thrombosis or for those who have the factor V Leiden mutation has the potential to reduce recurrent venous thromboembolism but also has the risk of major bleeding, including fatal bleeding.26 The relative risk-benefit of extending treatment beyond 6 months for selected patients with a first-episode of venous thromboembolism awaits the results of ongoing clinical trials. Further details of oral anticoagulant treatment are provided in Chap. 132.
Adjusted dose subcutaneous heparin is the long-term anticoagulant regimen of choice in pregnant patients (see Chap. 133 for further details). LMW heparin and heparinoids do not cross the placenta, and initial experience suggests these agents are safe for use in pregnant patients.28 However, controlled clinical trials comparing the efficacy and safety of LMW heparin with unfractionated heparin in pregnant patients have not been completed. It is also uncertain if the dosing regimens for LMW heparin evaluated by clinical trials in nonpregnant patients are generalizeable to the pregnant patient. LMW heparin has the advantages of causing less thrombocytopenia and potentially less osteoporosis than unfractionated heparin. However, routine use of LMW heparin for the pregnant patient is currently not recommended because of a lack of clinical trial data documenting efficacy and safety.28 Danaparoid is the preferred drug for pregnant patients with acute heparin-induced thrombocytopenia (HIT) or with a history of HIT who require anticoagulant treatment.28
LMW heparin given once daily by subcutaneous injection without monitoring is currently undergoing evaluation by clinical trials for the long-term treatment of deep-vein thrombosis.
THROMBOLYTIC THERAPY
Thrombolytic therapy is indicated for patients with pulmonary embolism who present with evidence of vascular collapse (hypotension and/or syncope) and for patients with pulmonary embolism who have clinical findings of right ventricular failure or echocardiographic evidence of right ventricular hypokinesis. Thrombolytic therapy provides more rapid lysis of pulmonary emboli and more rapid restoration of right ventricular function and pulmonary perfusion than anticoagulant treatment.29 An effective regimen is 100 mg of rtPA by intravenous infusion over 2 h (50 mg per h). Heparin is then given by continuous infusion once the thrombin time or activated partial thromboplastin time is less than twice control.29 The starting infusion dose is 1000 units/h. Further details of thrombolytic therapy are given in Chap. 134.
The role of thrombolytic therapy for patients with deep-vein thrombosis is currently very limited. Thrombolytic therapy may be indicated in patients with acute massive proximal-vein thrombosis (phlegmasia cerulea dolens with impending venous gangrene) or in the occasional patient with extensive ilieofemoral vein thrombosis who has severe symptoms due to venous outflow obstruction. Thrombolytic therapy can be given by systemic infusion or by catheter-directed infusion. It remains uncertain however whether systemic or catheter-directed thrombolysis will reduce the incidence of the postphlebitic syndrome.
INFERIOR VENA CAVA FILTER
Insertion of an inferior vena cava filter is indicated for (1) the patient with acute venous thromboembolism and an absolute contraindication to anticoagulant therapy, (2) the rare patient with massive pulmonary embolism who survives but in whom recurrent embolism may be fatal, (3) the rare patient who has objectively documented recurrent venous thromboembolism during adequate anticoagulant therapy, and (4) the patient with recent (<6 weeks) proximal-vein thrombosis who requires emergency surgery.
The insertion of a vena cava filter is effective for preventing important pulmonary embolism. However, the use of a filter results in an increased incidence of recurrent deep-vein thrombosis 1 to 2 years after insertion (increase in cumulative incidence at 2 years from 12% to 21%).30 If it is not contraindicated, long-term anticoagulant treatment should be administered after placement of a vena cava filter to prevent morbidity from recurrent deep-vein thrombosis.
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Hull R, Hirsh J, Carter C, et al: Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest 88:819, 1985.

9.
The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 263:2753, 1990.

10.
Birdwell BG, Raskob GE, Whitsett TL, et al: The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 128:1, 1998.

11.
Hull RD, Hirsh J, Carter CJ, et al: Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis. Ann Intern Med 102:21, 1985.

12.
Hull RD, Carter CJ, Jay RM, et al: The diagnosis of acute, recurrent deep-vein thrombosis: a diagnostic challenge. Circulation 67:901, 1983.

13.
Becker DM, Philbrick JT, Bachhuber TL, Humpries JE: D-dimer testing and acute venous thromboembolism: a shortcut to accurate diagnosis? Arch Intern Med 156:939, 1996.

14.
Turkstra F, van Beek EJR, ten Cate JW, Buller HR: Reliable rapid blood test for the exclusion of venous thromboembolism in symptomatic outpatients. Thromb Haemost 76:9, 1996.

15.
Bernardi E, Prandoni P, Lensing AW, et al: D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep-vein thrombosis: prospective cohort study. BMJ 317:1037, 1998.

16.
Perrier A, Desmarais S, Miron MJ, et al: Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 353:190, 1999.

17.
Hull R, Hirsh J, Sackett DL, et al: Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 64:622, 1981.

18.
Hull RD, Raskob GE, Ginsberg JS, et al: A noninvasive strategy for the treatment of patients with suspected pulmonary embolism. Arch Intern Med 154:289, 1994.

19.
Mayo JR, Remy-Jardin M, Muller NL, et al: Pulmonary embolism: prospective comparison of spiral CT with ventilation-perfusion scintigraphy. Radiology 205:447, 1997.

20.
Meaney JFM, Weg JG, Chenevert TL, et al: Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med 336:1422, 1997.

21.
Hyers TM, Agnelli G, Hull RD, et al: Antithrombotic therapy for venous thromboembolic disease. Chest 114:561s, 1998.

22.
Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA: Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 157:2562, 1997.

23.
Hull RD, Raskob GE, Brant RF, Pineo GF, Valentin KA: The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy: the emerging theme of delayed recurrence. Arch Intern Med 157:2317, 1997.

24.
Prandoni P, Lensing AWA, Cogo A, et al: The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 125:1, 1996.

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.
Schulman S, Granqvist S, Holmström M, et al: The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 336:393, 1997.

27.
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.

28.
Ginsberg JS, Hirsh J: Use of antithrombotic agents during pregnancy. Chest 114:524s, 1998.

29.
Goldhaber SZ, Haire WD, Feldstein ML, et al: Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 341:507, 1993.

30.
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.
Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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4 comments on “CHAPTER 129 VENOUS THROMBOSIS

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