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Published: December 2012

More information on this topic is available in the chapter: Hormone Therapy and the Risk of Venous Thromboembolism

Venous Thromboembolism
(Deep Venous Thrombosis & Pulmonary Embolism)

Asuka Ozaki

John R. Bartholomew

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Definition and Causes

Venous thromboembolism (VTE) is a disease that includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). It is a common, lethal disorder that affects hospitalized and nonhospitalized patients, recurs frequently, is often overlooked, and results in long-term complications including chronic thromboembolic pulmonary hypertension (CTPH) and the post-thrombotic syndrome (PTS).

Venous thromboembolism results from a combination of hereditary and acquired risk factors, also known as throm-bophilia or hypercoagulable states. In addition, vessel wall damage, venous stasis, and increased activation of clotting factors first described by Rudolf Virchow more than a century ago remain the fundamental basis for our understanding of thrombosis.

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Prevalence and Risk Factors

Venous thromboembolism is the third most common cardiovascular illness after acute coronary syndrome and stroke.1 Although the exact incidence of VTE is unknown, it is believed that there are approximately 1 million cases in the United States each year, many of which represent recurrent disease.2 Nearly two thirds of all VTE events result from hospitalization, and approximately 300,000 of these patients die.3 Pulmonary embolism is the third most common cause of hospital-related death and the most common preventable cause of hospital-related death.4,5 Most hospitalized patients have at least 1 or more risk factors for VTE (Table 1). Among hospitalized patients with acute medical illness, infection, age >75, cancer, and a history of VTE are MOST associated with an increased VTE risk.6 Long-established and well-known cardiovascular risk factors including hypertension, diabetes mellitus, cigarette smoking, and high cholesterol levels have also been linked to acute PE.7 Genetic risk factors for VTE include factor V Leiden, prothrombin gene mutation G20210A, protein C and S deficiency, and anti-thrombin deficiency.

Table 1. Pretest Probability of Deep Venous Thrombosis (Wells score)73
Clinical Feature* Score
Scoring
Active cancer (treatment ongoing or within previous 6 months of palliative treatment) 1
Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
Recently bedridden for >3 days or major surgery within 4 weeks 1
Localized tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling by >3 cm when compared with the asymptomatic leg (measured 10 cm below tibial tuberosity) 1
Pitting edema (greater in the symptomatic leg) 1
Collateral superficial veins (not varicose) 1
Alternative diagnosis as likely or more likely than that of deep-vein thrombosis -2
Analysis
High probability of DVT ≥3
Moderate probability of DVT 1 or 2
Low probability of DVT ≤0
Modified Score (adds 1 point if there is a previously documented DVT)
Likely ≥2
Unlikely ≤1

*In patients with symptoms in both legs, the more symptomatic leg is used.
DVT, deep venous thrombosis

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Pathophysiology and Natural History

Venous thrombi, composed predominately of red blood cells but also platelets and leukocytes bound together by fibrin, form in sites of vessel damage and areas of stagnant blood flow such as the valve pockets of the deep veins of the calf or thigh. Thrombi either remain in the peripheral veins, where they eventually undergo endogenous fibrinolysis and recanalization, or they embolize to the pulmonary arteries and cause PE.

Deep Venous Thrombosis

The lower extremities are the most common site for DVT, but other affected locations include the upper extremities and the mesenteric and pelvic veins, as well as the cerebral veins. A proximal lower-extremity DVT (defined as occurring in the popliteal vein and above) is linked to an estimated 50% risk of PE if not treated; while approximately 20% to 25% of calf vein thrombi propagate (in the absence of treatment) to involve the popliteal vein or above. Approximately 10% of all DVT cases involve the upper extremities. Complications are more common following DVT in the upper extremities than in the lower. Pulmonary embolism occurs in between 6% and 10% of cases following DVT in an upper extremity and in 15% to 32% of cases following DVT in a lower extremity.8

Pulmonary Embolism

Pulmonary emboli resulting from lower extremity DVT have the potential to lead to a number of physiologic changes due to obstruction of the pulmonary arteries. These include increased respiratory rate and hyperventilation, impairment of gas exchange due to impaired perfusion but not ventilation, intrapulmonary shunting leading to hypoxemia, and atelectasis and vasoconstriction resulting from the release of inflammatory mediators (serotonin and thromboxane).

In hemodynamically challenged patients, acutely elevated pulmonary vascular resistance results in decreased right ventricular (RV) output and hypotension. To overcome the obstructing thrombus and maintain pulmonary perfusion, the right ventricle must generate systolic pressures in excess of 50 mmHg and mean pulmonary artery pressures greater than 40 mmHg.9 The normal right ventricle, however, is unable to generate these pressures, and right heart failure and cardiac collapse ensues. Additionally, elevated RV wall tension can lead to decreased right coronary artery flow and ischemia. Cardiopulmonary collapse from PE is more common in patients with coexisting coronary artery disease or underlying cardiopulmonary disease.10

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Outcomes

More than 30% of patients who have an acute DVT develop PTS following the initial episode. Most develop signs and symptoms of this condition within 2 years of the acute event, and 5% to 10% will develop severe PTS with chronic venous stasis ulcer.11

Of the approximately 300,000 Americans who have a fatal PE each year, as many as 15% to 25% present with sudden death or die within 30 days of the diagnosis.12 The majority of patients die because of a failure in diagnosis rather than inadequate therapy. In fact, the mortality rate for PE without treatment is approximately 30%, whereas it is only 2% to 8% with adequate therapy.13 In addition, nearly 4% of all PE patients develop CTPH by the second year following the event.14

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Signs and Symptoms

Deep Venous Thrombosis

Typical symptoms of DVT in the upper and lower extremities include pain or tenderness and swelling. Signs on physical examination include increased warmth, edema, and erythema, and may also include dilated veins (collaterals) on the chest wall or leg. A limb-threatening manifestation of DVT, phlegmasia cerulea dolens, occurs most often in the setting of malignancy, heparin-induced thrombocytopenia (HIT), or other prothrombotic condition in which the thrombus completely occludes venous outflow, causing massive limb swelling, hypertension in the capillary bed, and eventually ischemia and gangrene if untreated.

Pulmonary Embolism

The most common signs and symptoms of acute PE include dyspnea, tachypnea, and pleuritic chest pain.15 Other reported findings include apprehension, hemoptysis, cough, syncope, and tachycardia. Fever, gallop, accentuation of the pulmonary closure sound, or an S3 and/or S4 rales, and leg erythema or a palpable cord may also be found.

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Diagnosis

Deep Venous Thrombosis

Clinical Decision Rules

The clinical examination of DVT is often unreliable; therefore, clinical decision rules (pretest probability scores) based on the patient’s signs, symptoms, and risk factors have been developed to stratify patients into low, moderate, or high clinical probability.16-20 This approach helps to improve the effectiveness of diagnosing DVT and to limit the need for additional testing. Using a clinical decision rule (as in Table 2), patients in the low pretest probability category have a 96% negative predictive value for DVT (99% if the D dimer is negative as well). The positive predictive value in patients with a high pretest probability is less than 75%, supporting the need for further diagnostic testing to identify patients with an acute thrombosis.17-20 A clinical prediction score has also been developed for upper extremity DVT using the presence of a pacemaker or a catheter or access device in the internal jugular or subclavian veins, localized pain, unilateral pitting edema, or another diagnosis at least as plausible as independent predictors for DVT.21

Table 2. Major Risk Factors for Venous Thromboembolism73
Hereditary Risk Factors
Antithrombin deficiency
Dysfibrinogenemia
Elevated levels of factor VIII
Factor V Leiden mutation
Hyperhomocysteinemia
Protein C or S deficiency
Prothrombin gene mutation
Acquired Risk Factors
Air travel
Antiphospholipid syndrome
BMI >30
Cancer or certain cancer treatments
Cardiovascular risk factors (smoking, hypertension, hyperlipidemia, diabetes mellitus)
Heparin-induced thrombocytopenia
Immobilization
Indwelling central venous catheters or pacemakers
Inflammatory bowel disease
Medical illness (heart failure, chronic obstructive pulmonary disease)
Myeloproliferative disorders
Pregnancy, oral contraceptives, hormone replacement therapy
Presence of an IVC filter
Previous episode of venous thromboembolism
Surgery
Trauma

BMI, body mass index; IVC, inferior vena cava

D-Dimer Testing for DVT

The sensitivity and negative predictive value of D-dimer assays are high, and their specificity is low. A positive D dimer, however, does not confirm the diagnosis of DVT. False-positive levels are seen in patients with malignancy, trauma, recent surgery, infection, pregnancy, and active bleeding.

Duplex Ultrasonography

Duplex ultrasonography is the imaging procedure of choice for the diagnosis of DVT because it is readily available and is less invasive and less costly than other procedures. It has a sensitivity and specificity of about 95% and 98%, respectively, for detecting DVT in symptomatic patients; however, it is operator dependent and less sensitive in asymptomatic patients and for detecting calf vein thrombi.22,23 Duplex ultrasonography cannot always distinguish between acute and chronic DVT and may be difficult to perform on obese patients. An inability to compress the vein with the ultrasound transducer is considered diagnostic for DVT. Other findings that are suggestive but not diagnostic include venous distention, absent or decreased spontaneous flow, and abnormal Doppler signals.24

Contrast Venography

Contrast venography was the gold standard test for the diagnosis of DVT. The presence of an intraluminal filling defect is diagnostic, although abrupt cutoffs, non-filling of the deep venous system, or demonstration of collateral flow may raise suspicion for the presence of DVT. Venography is invasive and requires the use of potentially harmful contrast agents; therefore, it has largely been replaced by noninvasive tests.

Other Diagnostic Tests

Less frequently used tests to detect DVT include magnetic resonance venography (MRV) imaging and computed axial tomography venography.

Pulmonary Embolism

Clinical Decision Rules

Pretest probability scores or clinical decision rules have also been developed to aid in the diagnosis of acute PE.25 (Table 3). There are a number of clinical decision rules available including the Wells rule and the Geneva score. Both have original and simplified versions.26 These clinical decision rules are similar to those employed for DVT; using signs, symptoms, and risk factors to calculate a low, moderate, or high pretest probability score. In a validation study using this approach in combination with a negative D-dimer test, only 0.5% of patients who were thought unlikely to have a PE later developed nonfatal VTE.27

Table 3. Clinical Decision Rules (Pre-test Probability for Pulmonary Embolism)56
Variable Points
Clinical signs and symptoms of DVT (minimal leg swelling and pain with palpation of the deep veins 3.0
Alternative diagnosis less likely than PE 3.0
Heart rate >100 bpm 1.5
Immobilization >3 days or surgery in the previous week 1.5
Previous PE or DVT 1.5
Hemoptysis 1.0
Malignancy (receiving treatment or treated in past 6 months or palliative) 1.0

Key: Low probability, <2.0; moderate probability, 2.0-6.0; high probability >6.0.
BPM, beats per minute; DVT, deep venous thrombosis; PE, pulmonary embolism

D-Dimer Testing for PE

Patients with a low pretest probability score for PE and negative D-dimer have a high negative predictive value similar to that observed in patients with DVT. However, the patient who has an intermediate to high pretest probability score with a negative D-dimer requires further diagnostic testing to exclude PE.28

Electrocardiography

The major utility of electrocardiography (ECG) in the diagnosis of PE is to rule out other major diagnoses, such as acute myocardial infarction (MI). The most specific finding on ECG is the classic S1Q3T3 pattern, but the most common findings consist of nonspecific ST-segment and T-wave changes. Other commonly reported but nonspecific findings include sinus tachycardia, atrial fibrillation, and right bundle-branch block.29

Chest Radiography

Chest radiography may also be more helpful in establishing other diagnoses. The most common findings are nonspecific and include pleural effusion, atelectasis, and consolidation.

Arterial Blood Gas Determination

Pulmonary embolism can result in significant hypoxia, and in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, only 26% of patients with angiographically proven PE had a PaO2 greater than 80 mmHg.30 Therefore, a normal PaO2 cannot rule out PE; however, hypoxia in the absence of cardiopulmonary disease should raise suspicion for this diagnosis. In patients with cardiopulmonary collapse, a normal PaO2 suggests an alternative diagnosis. Similarly, an elevated alveolar-arterial gradient is suggestive but not specific for the diagnosis of an acute PE. Therefore if the alveolar-arterial gradient is normal, an acute PE cannot be excluded.31

Computed Tomographic Pulmonary Angiography

Because of its wide availability and ability to visualize thrombus directly, computed tomographic pulmonary angiography (CTPA) imaging has become the standard imaging technique for diagnosing PE. Although initially considered useful only for evaluating central PE and not thought to be the equal to ventilation perfusion (V/Q) scanning, the sensitivity and specificity of newer CTPA scans with multiple slices has increased greatly for diagnosing smaller peripheral or subsegmental PEs. In a study by Anderson and colleagues, patients were randomly assigned to undergo either PTCA or V/Q scanning. The results suggested that CTPA was more sensitive than V/Q scans.32

CTPA also allows direct imaging of the inferior vena cava and the pelvic and leg veins, and can identify other pathologies that can mimic acute PE. The major disadvantages of CTPA are radiation exposure, higher cost, and the possibility of contrast-induced nephrotoxicity. In a meta-analysis of 23 studies involving 4,657 patients with suspected PE who had a normal CTPA, only 1.4% developed VTE and 0.51% developed fatal PE by 3 months.33 These rates are similar to those seen in studies of patients with suspected PE who had normal pulmonary angiograms.34 CTPA can also identify right ventricle enlargement (defined as a ratio of right ventricle diameter to left ventricle diameter >0.9), which has been shown to predict adverse clinical events. This procedure may be an alternative to echocardiography for diagnosing RV enlargement.35

Ventilation-Perfusion Scanning

Ventilation-perfusion scanning is now considered a second-line imaging method for the diagnosis of PE. It is helpful in patients who have normal chest radiography or who are unable to undergo CTPA (patients with renal insufficiency, contrast allergy, obesity, or pregnancy). A normal perfusion scan rules out the diagnosis of PE, whereas a high-probability scan along with a high degree of clinical suspicion is diagnostic. Unfortunately, nondiagnostic lung scans (intermediate or low probability) are the most common, and in the PIOPED study they occurred in 72% of patients, thereby limiting the usefulness of this modality.36 It must also be noted that in PIOPED, patients with a high or intermediate clinical suspicion for PE but a low-probability scan had a 40% and 16% rate of PE diagnosed by pulmonary angiography, respectively.36 Hence, it is currently advised that patients with a high or intermediate clinical suspicion for PE but a low-probability V/Q scan have additional tests to confirm or exclude the diagnosis. More recently, PIOPED II, using a different classification system (present or absent) reported that 21% of studies were nondiagnostic leading the authors to suggest that the lung scan may be making a revival.37

Biomarkers (Troponins and Brain Natriuretic peptide)

Elevated levels of cardiac troponins correlate with echocardiographic findings of RV pressure overload in patients with acute PE and overall mortality. In-hospital complications are more frequent in these patients compared to patients with normal levels.38 Brain natriuretic peptide (BNP) elevation in the absence of renal dysfunction is also a marker of RV dysfunction in patients with PE and has been shown to predict adverse outcome in patients with acute PE.39

Echocardiography (Transthoracic and Transesophageal)

More than 50% of hemodynamically stable patients with PE do not have evidence of RV dysfunction on transthoracic echocardiography (TTE).40 Patients with hemodynamic collapse, however, generally suffer severe RV dysfunction, and TTE or transesophageal echocardiography (TEE) can provide rapid bedside assessment in these critically ill patients who are at increased risk for death. Echocardiography findings include RV dilatation, RV hypokinesis, tricuspid regurgitation, septal flattening, paradoxical septal motion, diastolic left ventricular impairment resulting from septal displacement, pulmonary artery hypertension, lack of inspiratory collapse of the inferior vena cava, and occasionally direct visualization of the thrombus. In patients with large PE, it has been observed that despite moderate or severe RV free-wall hypokinesis there is relative sparing of the apex. This finding is referred to as McConnell’s sign and has a specificity of 94% and a positive predictive value of 71% for acute PE.41 McConnell’s sign may be useful in discriminating RV dysfunction resulting from PE from that of other causes.

Pulmonary Angiography

Pulmonary angiography remains the reference standard diagnostic test for PE, but it has been used infrequently since the advent of CTPA. It is invasive, costly, and associated with nephrotoxicity due to contrast exposure; however, in experienced centers, associated morbidity and mortality are low. An intraluminal filling defect or an abrupt cutoff of a pulmonary artery is considered diagnostic.

Magnetic Resonance Angiography

Magnetic resonance angiography (MRA) may be an alternative to CTPA for the diagnosis of PE in patients who have contrast allergy or for whom avoidance of radiation exposure is desired. Reports of sensitivity and specificity are varied but compared to CTPA, MRA has been reported to be both less sensitive and less specific and limited by interobserver variability.42

Summary

The American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP) have published a clinical practice guideline that summarizes current approaches for the diagnosis of venous thromboembolism.43

  • Clinical prediction rules should be used to estimate the pretest probability of DVT and PE.
  • In selected patients with a low pretest probability of DVT or PE, a negative high-sensitivity D-dimer test indicates a low likelihood of VTE.
  • Ultrasound is recommended for patients with intermediate to high pretest probability of DVT in the legs.
  • Patients with intermediate or high pretest probability of PE require additional diagnostic imaging studies.

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Treatment

The main goals of treatment for DVT include prevention of PE, the PTS, and recurrent thrombosis. Once VTE is suspected, anticoagulation should be started immediately unless there is a contraindication.

Medical Management: Anticoagulation

Initial therapy may include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux followed by an oral anticoagulant (vitamin K antagonist [VKA]). Early initiation of a VKA on the first day of parenteral therapy is advised.44

Risk stratification is essential for managing acute PE. The clinical examination (including blood pressure, heart rate, and oxygen saturation) biomarkers (troponin, BNP), and echocardiography to assess the right ventricle and PE size should all be used to assist in the acute management of PE.45 If the patient is normotensive and the right ventricle size and function are normal, standard anticoagulation is advised. If the patient is normotensive, but the right ventricle is abnormal and biomarkers are elevated, treatment is more controversial. For the patient who is hemodynamically unstable, thrombolysis or pulmonary embolectomy should be considered.44,45

Unfractionated Heparin

Weight-based dosing of UFH (80 U/kg bolus followed by 18 U/kg/hr IV infusion) has been shown to achieve a therapeutic activated partial thromboplastin time (aPTT) more rapidly than fixed-dose regimens. The target aPTT has traditionally been 1.5 to 2.5 times the control aPTT; however, the actual aPTT in seconds varies among laboratories because of the use of different thromboplastin reagents. The American College of Chest Physicians (ACCP) and College of American Pathologists recommend that a therapeutic aPTT range be calibrated for each laboratory by determining the aPTT values that correlate with therapeutic UFH levels of 0.3 to 0.7 IU/mL as determined by factor Xa inhibition.

The aPTT should not be followed in patients with an abnormal baseline aPTT (eg, in patients with a lupus anticoagulant), in patients who require unusually high doses of UFH such as those with antithrombin deficiency, and in selected patients with an underlying malignancy, or during pregnancy. In these situations, the anti–factor Xa assay should be used.

Unfractionated heparin can also be administered subcutaneously as an alternative to IV administration, and 2 dosing regimens have been recommended. One approach uses an initial IV bolus of 5000 U of UFH followed by a subcutaneous dose of 17,500 U twice daily.45 An aPTT is drawn 6 hours after the initial dose, and subsequent doses are adjusted accordingly to achieve a therapeutic aPTT. Another approach recommends a subcutaneous loading dose of 333 U/kg of UFH followed by fixed doses of 250 U/kg subcutaneously every 12 hours without the need for aPTT monitoring.46

Low-Molecular-Weight-Heparin

LMWH is administered as a weight-based subcutaneous injection. In the current ACCP guidelines, LMWH is recommended over UFH for the initial treatment of DVT or PE.44 Enoxaparin, the most commonly used agent in the US, is given either as a once-daily injection (1.5 mg/kg/day) or twice daily (1 mg/kg every 12 hr). LMWH is the preferred agent for patients with malignancy.47 Two other agents are available, dalteparin and tinzaparin. LMWH is renally cleared, and can be given in patients with renal insufficiency (defined as a creatinine clearance of less than 30 mL/minute) after dose adjustment. No monitoring is required although it is advised in patients with renal insufficiency, or in obese, pediatric, or pregnant patients. If monitoring is required, an anti-Xa level using LMWH as a reference standard should be measured 4 hours after a subcutaneous injection. Therapeutic range is 0.5 to 1.0 IU/mL for the 12-hour regimen and 1.0 IU/mL for the once-daily dose.

Factor Xa Inhibitors

Fondaparinux is an indirect factor Xa inhibitor that can be used as VTE prophylaxis in medical patients, those undergoing orthopedic procedures (total hip and knee arthroplasty), and those undergoing abdominal surgery. It is also approved as treatment for acute DVT and PE when used in combination with a VKA. In the most recent ACCP guidelines, fondaparinux is recommended over UFH for the initial treatment of DVT or PE.44 Its efficacy and safety in comparison to LMWH for the treatment of acute DVT and in comparison with IV UFH for the treatment of PE has been shown in large randomized, controlled trials.48,49 Fondaparinux is administered as a once-daily subcutaneous injection of 2.5 mg for DVT prophylaxis and 5 mg, 7.5 mg, or 10 mg based on body weight (<50 kg, 50-100 kg, >100 kg, respectively) for the treatment of DVT or PE.50 Fondaparinux is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) and bacterial endocarditis.50 Several case reports of HIT due to fondaparinux, without exposure to UFH or LMWH, have been reported.51

Warfarin

Warfarin remains the mainstay of therapy for long-term treatment of VTE. It may be initiated once anticoagulation with UFH, LWMH, or fondaparinux has been started (and which should be continued as overlap treatment for a minimum of 5 days and until the international normalized ratio [INR] is at least 2.0 for 24 hours).44 Data suggest that individual variability in response to warfarin dose during initial anticoagulation and time to therapeutic INR may be influenced by genetic variations in the pharmacologic target of warfarin.52 Physicians are now able to identify whether patients require low, intermediate, or high doses of warfarin, potentially minimizing complications of under- or overdosing (thrombosis or bleeding). A recent study has demonstrated that monitoring warfarin every 12 weeks is safe and non-inferior to every 4 weeks making warfarin more attractive to those patients who prefer less frequent monitoring.53

New Oral Anticoagulants

Dabigatran (direct thrombin inhibitor) and rivaroxaban (factor Xa inhibitor) have been studied extensively and shown to be non-inferior to VKA for treatment of VTE.54 Rivaroxaban has been approved by the FDA for use in the prevention of VTE for the patient undergoing total hip or knee replacement surgery. It has also been approved for the treatment of DVT and PE based on clinical trials. In studies comparing rivaroxaban to enoxaparin and a VKA, rivaroxaban was as effective for treatment of VTE. The drug is given orally once daily and is contraindicated in patients with renal insufficiency. The major side effect observed with rivaroxaban is bleeding, similar to other anticoagulants.55

Thrombolytic Therapy

Thrombolytic therapy for DVT may be beneficial in selected patients, and although it can be administered systemically, local infusion under catheter directed therapy (CDT) is preferred. Both routes carry an increased risk of hemorrhage compared to standard anticoagulation. The current ACCP guidelines advise anticoagulant therapy over CDT, The guidelines suggest that patients who are most likely to benefit from CDT and who place high importance on preventing the PTS choose CDT over anticoagulation alone.56 This is in contrast to the 2008 CHEST guidelines that recommended patients with extensive proximal DVT, with high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status, be given CDT if the expertise and resources are available.44 Although it has been suggested that use of thrombolytics promotes early recanalization and minimizes the incidence of the PTS, their role in the treatment of DVT without a threatened limb is unclear. An NIH-sponsored trial, the ATTRACT study, is ongoing to answer this question.

Thrombolytic therapy for acute PE remains controversial because there has been no clearly established short-term mortality benefit. Because of favorable outcomes with prompt recognition and anticoagulation for PE, thrombolysis should be reserved for hemodynamically unstable patients with acute PE and a low risk of bleeding. An area of ongoing debate is whether there is benefit for thrombolytic therapy in patients who are hemodynamically stable but have echocardiographic evidence of right ventricle dysfunction.

Streptokinase, administered as a 250,000 IU loading dose followed by 100,000 IU/hr for 24 hours and tissue plasminogen activator (rtPA) given as a 100-mg infusion over 2 hours are the current agents approved by the FDA. The ACCP guidelines recommend systemic thrombolytic therapy using an agent with a short infusion time in patients who are hemodynamically unstable. Bleeding remains the most serious complication of thrombolytic therapy. Local administration of these agents via catheter-directed therapy is recommended over a pulmonary artery catheter.44 The risk of intracranial bleeding is 1% to 2%.

Surgical/Mechanical intervention

Pulmonary Embolectomy

According to ACCP guidelines, pulmonary embolectomy for the initial treatment of PE is reserved for patients with massive PE (documented angiographically if possible), shock despite heparin and resuscitation efforts, and failure of thrombolytic therapy or a contraindication to its use.44 To date, there have been no randomized trials evaluating this procedure. Pooled data published by Stein and colleagues report a 20% operative mortality rate in patients undergoing pulmonary embolectomy between 1985 and 2005 compared to 32% in patients undergoing the procedure before 1985.57

Other investigational therapies include catheter-based embolectomy procedures that use aspiration, fragmentation, or rheolytic therapy. The current ACCP guidelines advise catheter-based thrombus removal should be considered in patients with acute PE and hypotension in whom thrombolysis has failed─or in whom it is contraindicated─or those who have shock that is likely to cause death before systemic thrombolysis can take effect.56

Vena Caval Interruption

Current guidelines recommend against the routine use of inferior vena cava (IVC) filters for the treatment of VTE. Indications for the placement of IVC filters include a contraindication to anticoagulation, complications of anticoagulation, recurrent thromboembolism despite adequate anticoagulant therapy, and patients undergoing pulmonary embolectomy.44 Relative indications for IVC filters are massive PE, iliocaval DVT, free-floating proximal DVT, cardiac or pulmonary insufficiency, high risk of complications from anticoagulation (frequent falls, ataxia), or poor compliance. Retrievable filters may be considered for situations where anticoagulation is temporarily contraindicated or there is a short duration of PE risk.58 The current consensus guidelines advise that indications for placing a retrievable IVC filter are the same as for placing permanent devices.58 An IVC filter alone is not effective therapy for DVT, and resumption of anticoagulation as soon as possible after placement is recommended.

Duration of Treatment

The duration of treatment following the diagnosis of VTE depends on the risk of recurrence. Risk factors for recurrence include idiopathic DVT or PE, certain underlying hypercoagulable states such as the antiphospholipid syndrome, and underlying malignancy. Additional risk factors include placement of a permanent IVC filter, elevated D-dimer levels following discontinuation of warfarin, advanced age, male sex, and increased BMI (Table 4). Although the risk of recurrence decreases with longer durations of anticoagulation, clinicians must weigh the risk of bleeding against the risk of new thrombosis.

Table 4. Risk Factors for Recurrence of Venous Thromboembolism
Male sex
Increasing age
Increasing body mass index
Neurologic disease (with extremity paresis)
Malignancy
Antiphospholipid syndrome
Idiopathic VTE
Strong family history of VTE
Antithrombin, protein C and S deficiencies
Homozygous for factor V Leiden
Doubly heterozygous for factor V Leiden and prothrombin gene mutation
Elevated D dimer following discontinuation of warfarin
Permanent IVC filter

DVT, deep venous thrombosis; IVC, inferior vena cava; VTE, venous thromboembolism

Current guidelines recommend 3 months of anticoagulation with a VKA targeting an INR of 2 to 3 for patients with an episode of DVT or PE resulting from a transient cause.44 Patients who have the antiphospholipid syndrome, who are homozygous for factor V Leiden, or who are doubly heterozygous for factor V Leiden and prothrombin gene mutation should be considered for longer periods of anticoagulation. Long-term (indefinite) anticoagulation is also recommended in patients with malignancy as long as the cancer remains active and in patients who have unexplained recurrent VTE.44

The duration of treatment for unprovoked VTE remains controversial. Current guidelines recommend that patients be treated for 3 months, but be considered for indefinite or long-term anticoagulation depending on the risk-benefit ratio of extended therapy.56 Use of markers such as residual venous obstruction (RVO) and D-dimer level have been studied in an effort to predict the risk of recurrence and thus the duration of anticoagulation.59,60 RVO appears to be less helpful than the D-dimer level as an indicator for recurrence. The DASH prediction score may help to calculate recurrence risk based on the following predictors: abnormal D-dimer 3 weeks after stopping anticoagulation, age <50 years, male sex, and hormone use at the time of the VTE. It appears to predict recurrence risk in patients with a first unprovoked DVT. This may help the physician decide whether to continue anticoagulation therapy.44,61

Compression Stockings

Damage to the venous valves from DVT can lead to venous hypertension and result in the development of PTS characterized by edema; skin changes, including increased pigmentation and lipodermatosclerosis; pain; and, in severe cases, venous stasis ulceration. The incidence of PTS has been drastically reduced with the use of compression stockings. Current ACCP guidelines recommend the of compression stockings at a pressure of 30 mmHg to 40 mmHg for 2 years following an acute episode of DVT. The American College of Physicians and the American Academy of Family Physicians recommend use for 1 year.6244,62

Summary

The ACP and the AAFP have published clinical practice guidelines that summarize current approaches for treating VTE.63

  • LMWH should be chosen over UFH if possible for the initial inpatient treatment of DVT; either UFH or LMWH is acceptable for PE.
  • Outpatient treatment of DVT and possibly PE with LMWH is safe and cost effective for carefully selected patients.
  • Compression stockings should be used to prevent the PTS, beginning within 1 month of diagnosis of a proximal DVT and continued for at least 1 year after diagnosis.
  • Both the ACP and the AAFP have found that there is insufficient evidence to make specific recommendations for types of anticoagulation for the treatment of VTE in pregnant patients.
  • Anticoagulation should be given for 3 to 6 months for DVT or PE that results from transient risk factors and for more than 12 months for recurrent VTE. Extended-duration therapy is advisable in patients with an idiopathic VTE.
  • LMWH is safe and effective for the long-term treatment of VTE in selected individuals and may be preferable for cancer patients.

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Prevention and Screening

Prevention

Approximately two-thirds of all VTE events result from hospitalization, yet only one third of all hospitalized patients at risk receive adequate prophylaxis.2 PE is the most common preventable cause of hospital death in the US. Without prophylaxis, the incidence of hospital-acquired DVT is 10% to 20% among medical patients and higher (15% to 40%) among surgical patients.64 Adequate prophylaxis can reduce the incidence of VTE as demonstrated in a meta-analysis involving 19,958 patients. There was a 62% reduction in fatal PE, 57% reduction in fatal and nonfatal PE, and 53% reduction in DVT.64

The consequences of VTE if not prevented include symptomatic DVT and PE, fatal PE, the cost of investigating symptomatic patients, the risk and cost of treatment (bleeding), PTS, and CTPH. Heparin, enoxaparin, fondaparinux are approved for prophylactic use in medical and surgical patients. Warfarin with a target INR of 2.5 and the factor Xa inhibitor, rivaroxaban, are approved for use in patients undergoing total knee/hip replacement. For patients with increased bleeding risk who are unable to receive pharmacologic prophylaxis, intermittent pneumatic compression devices or graduated compression stockings should be used.

In addition to anticoagulants, the JUPITER trial showed that statins reduce the risk of symptomatic VTE in apparently healthy patients.65 However, statins should not substitute for proven prophylaxis and anticoagulation.66 Aspirin is also shown to prevent the recurrence of first unprovoked VTE by 40% if used after completion of anticoagulation.67

Screening

Screening asymptomatic patients for DVT is labor intensive and cost ineffective.68-71 Thus, prophylaxis in at-risk populations remains the most effective means for preventing complications of VTE.64

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Considerations in Special Populations

Calf Vein Thrombosis

Treatment of calf vein thrombosis is more controversial. Anticoagulation is generally indicated for patients with an isolated calf DVT related to surgical or transient risk factors. The recommended duration of treatment is 3 months, with a VKA targeting an INR of 2 to 3.

Monitoring calf vein thrombosis for propagation into the proximal veins (popliteal vein or above) with serial ultrasonography (once weekly for 2 weeks) without anticoagulation represents an alternative approach for managing patients with a contraindication to anticoagulation or asymptomatic isolated distal DVT. Because of the controversy over no treatment versus treatment, investigations are ongoing to evaluate the efficacy and safety of anticoagulation therapy in isolated calf vein DVT.72

Superficial Venous Thrombosis

Superficial venous thrombosis (SVT) often occurs as a complication of an intravenous line, but can occur spontaneously. Anticoagulation is recommend for SVTs longer than 5 cm in length with prophylactic doses of an anticoagulant such as fondaparinux 2.5 mg for at least 45 days.

Deep Venous Thrombosis of the Upper Extremity

Upper-extremity DVT is most often related to central venous catheter placement, pacemaker devices, or intravenous drug abuse. Other, less common causes include thoracic outlet syndrome (also referred to as effort thrombosis) and hypercoagulable conditions including malignancy. Patients may be asymptomatic, but more often they complain of arm swelling and pain. Anticoagulation is indicated if the DVT is in the internal jugular, axillary or subclavian or innominate veins for 3 months or as long as the catheter is in place. Thrombolysis should be considered in younger patients (especially those with thoracic outlet syndrome) with a low risk of bleeding and symptoms of acute onset.44

Phlegmasia Cerulea Dolens

Phlegmasia cerulea dolens is a vascular emergency requiring anticoagulation or, in selected cases, thrombolysis or surgical or catheter-based thrombectomy. Fasciotomy may also be required to relieve associated compartment syndromes. This condition, as mentioned previously, is seen in patients with an underlying malignancy or HIT.

Pregnancy and Venous Thromboembolism

Venous thromboembolism is the leading cause of maternal death. The risk of VTE during pregnancy is increased 4-fold, but the risk is increased 5-fold for the 6 weeks following delivery. Increased risks for VTE during pregnancy include age older than 35 years, cesarean section, pre-eclampsia, and a history of previous VTE or family history of thrombosis. LMWH is the anticoagulant of choice during pregnancy.

Summary

  • Venous thromboembolism is the third most common cardiovascular disease after MI and stroke.
  • Long-term complications include recurrent VTE, CTPH, and the PTS.
  • The recurrence rate for idiopathic VTE approaches 30% after 10 years, the incidence of CTPH is 4% at 2 years, and the rate of PTS is 30% at 8 years.
  • D dimer is an excellent test to exclude VTE.
  • Duplex ultrasonography is the noninvasive test of choice for the diagnosis of DVT.
  • Computed tomographic pulmonary angiography has replaced the ventilation perfusion scan for diagnosing PE.
  • Risk stratification is the key to management of patients with VTE.
  • Indefinite anticoagulation should be considered for patients with an idiopathic or unprovoked VTE.
  • Appropriate prophylaxis remains underused.

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