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 thrombophilia 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 still 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 there are approximately 1 million cases of VTE 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 it is the most common preventable cause of hospital-related death.^{4, 5} Most hospitalized patients have at least one or more risk factors for VTE (Box 1). Long-established and well-known cardiovascular risk factors including hypertension, diabetes mellitus, cigarette smoking, and high cholesterol levels have been linked to acute PE.⁶

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Pathophysiology and natural history

Venous thrombi, composed predominately of red blood cells but also platelets and leukocytes all 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. A proximal lower-extremity DVT (defined as the popliteal vein and above) has an estimated risk of 50% for PE if not treated; approximately 25% of calf vein thrombi propagate (in the absence of treatment) to involve the popliteal vein or higher.

Pulmonary Embolism

Pulmonary emboli commonly result from lower extremity DVTs. These thrombi have the potential to lead to a number of physiologic changes due to their 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.⁷ 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 .⁸

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Outcomes

Close to 30% of patients who have an acute DVT develop the PTS by year 8 following their initial episode.⁹ Most develop signs and symptoms of this condition within 2 years of their acute event, and nearly 25% develop a chronic venous stasis ulcer.

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 their diagnosis.¹⁰ 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.¹¹ In addition, nearly 4% of all PE patients develop CTPH by the second year following their event.¹²

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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 the presence of 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 thrombophilic conditions 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.¹³ Other reported findings include apprehension, hemoptysis, cough, syncope, and tachycardia. Fever, gallop heart sounds (S₃ and/or S₄), accentuation of the pulmonary closure sound, 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.^{14, 15-18} This approach helps to improve the effectiveness of diagnosing DVT as well as limiting the need for additional testing. Using the clinical decision rule (Table 1), patients in the low pretest probability category have a 96% negative predictive value for DVT (99% if the D dimer is negative as well), and 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.^15-18

D-Dimer Testing

The sensitivity and negative predictive value of D-dimer assays are high, and their specificity is low. The combination of a low pretest probability or clinical decision rule and a negative D dimer has an extremely high negative predictive value for VTE (approximately 99%).¹⁸ 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.^{19, 20} 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.²¹

Contrast Venography

Contrast venography has been the gold standard test for the diagnosis of DVT. The presence of an intraluminal filling defect is diagnostic, although abrupt cutoffs, nonfilling 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 imaging (MRV) 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.²² (Table 2). This approach is similar to that 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, only 0.5% of patients who were thought unlikely to have a PE later developed nonfatal VTE.²³

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 an 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.²⁴

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 mm Hg.²⁵ Therefore, a normal Pao₂ cannot rule out PE; however, hypoxia in the absence of cardiopulmonary disease should raise the 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.²⁶

Computed Tomographic Pulmonary Angiography

Because of its wide availability and its ability to directly visualize thrombus, 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 () scanning, the sensitivity and specificity of newer CTPA scans with multiple slices has increased greatly for diagnosing smaller peripheral or subsegmental PEs. In a recent study by Anderson and colleagues, patients were randomized to undergo PTCA or scanning. Their results suggested that CTPA was even more sensitive that scans.²⁷

CTPA also allows direct imaging of the inferior vena cava and the pelvic and leg veins, as well as identifying 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 suspicion for PE who had a normal CTPA, only 1.4% developed VTE and 0.51% developed fatal PE by 3 months.²⁸ These rates are similar to studies of patients with suspected PE who had normal pulmonary angiograms.²⁹ Computed tomographic pulmonary angiography 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.³⁰

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 patients who are unable to undergo CTPA (patients with renal insufficiency, contrast allergy, or pregnancy). A normal perfusion scan rules out the diagnosis of a PE, whereas a high-probability scan in the setting of a high 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 their usefulness.³¹ 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.³¹ Hence, it is currently advised that patients with a high or intermediate clinical suspicion for PE but a low-probability scan have additional tests to confirm or exclude the diagnosis.

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 higher in these patients compared to those with normal levels.³² Brain natriuretic peptide (BNP) elevation in the absence of renal dysfunction is also a marker of RV dysfunction in patients with PE and has also been shown to predict adverse outcome in patients with acute PE.³³

Echocardiography (Transthoracic and Transesophagel)

More than 50% of hemodynamically stable patients with PE do not have evidence of RV dysfunction on transthoracic echocardiography (TTE).³⁴ 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 secondary to 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.³⁵ McConnel's sign may be useful in discriminating RV dysfunction resulting from PE versus other causes.

Pulmonary Angiography

Pulmonary angiography remains the reference standard diagnostic test for PE, but it is used infrequently since the advent of CTPA. It is invasive, costly, and associated with nehphrotoxicity 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 interoberserver variability.³⁶

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Summary

The American Academy of Family Physicians and the American College of Physicians have published a clinical practice guideline that summarizes current approaches for the diagnosis of venous thromboembolism.³⁷

• Clinical prediction rules should be used to estimate the pretest probability of DVT and PE.
• In select patients with a low pretest probability of DVT or PE, a negative high-sensitivity D-dimer 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 DVT is suspected, anticoagulation should be started immediately unless there is a contraindication.

Anticoagulation

Initial therapy may include heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux (Arixtra) followed by an oral anticoagulant (vitamin K antagonist or VKA). LMWH and fondaparinux are renally cleared. The LMWHs can be given in patients with renal insufficiency after dose adjustment; fondaparinux is contraindicated if the creatinine clearance is less than 30 mL/min. Both agents are contraindicated in patients requiring dialysis.

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 (e.g., in patients with a lupus anticoagulant), in patients who require unusually high doses of UFH such as those with antithrombin deficiency, in select patients with an underlying malignancy, or during pregnancy. In these situations, the anti–factor Xa assay should be used.

Unfractionated heparin can also be administed subcutaneously as an alternative to IV administration, and two dosing nomograms have been recommended. One approach uses an initial IV bolus of 5000 U of UFH followed by a subcutaneous dose of 17, 5000 U twice daily.⁴⁴ An aPTT is drawn 6 hours after the initiation dose, and subsequent doses are adjusted accordingly to achieve a therapeutic aPTT. Another recently derived nomogram 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.³⁸

Low-Molecular-Weight-Heparin

LMWH is administered as a weight-based subcutaneous injection. Enoxaparin, the most commonly used agent in the United States, is given either as a once-daily injection (1.5 mg/kg/day) or twice per day (1 mg/kg every 12 hr). Two other agents are available, dalteparin and tinzaparin. No monitoring is required except in 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 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. 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.^{39, 40} 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. Fondaparinux is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) and bacterial endocarditis.⁴² A case of HIT due to fondaparinux, without exposure to UFH or LMWH, has been reported.⁴²

Once anticoagulation with UFH, LMWH, or fondaparinux is begun, a VKA may be initiated. An overlap should be continued for a minimum of 5 days and until the international normalized ratio (INR) is within the target range of 2.0 to 3.0 for 24 hours to permit adequate depletion of vitamin K–dependent coagulation factors.⁴³

Thrombolytic Therapy

Thrombolytic therapy for DVT may be beneficial in select patients, and although it can be administered systemically, local infusion under catheter guidance is preferred. Both routes carry an increased risk of hemorrhage compared to standard anticoagulation. 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 still unclear. The current ACCP guidelines suggest that in selected patients with extensive proximal DVT who are at low risk of bleeding and who otherwise have good functional status and life expectancy of 1 year, catheter-directed thrombolysis may be considered if the expertise and resources are available.⁴³

Pulmonary Embolism

Once the diagnosis of PE is suspected, UFH, LMWH, or fondaparinux should be started immediately, unless their use is contraindicated. Anticoagulation with any of these agents should be followed by the addition of a VKA.⁴⁴ Risk stratification is felt to be essential for managing acute PE. According to Goldhaber, 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.⁴⁴ 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 as noted by the ACCP guidelines. For the patient who is hemodynamically unstable, however, thrombolysis or pulmonary embolectomy should be considered.⁴⁴

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 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 not recommended due to the risk of hemorrhage at the insertion site.⁴³ The risk of intracranial bleeding is 1% to 2%.

Pulmonary Embolectomy

According to the 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 in patients undergoing pulmonary embolectomy from 1985 to 2005.⁴⁵

Other investigational therapies include catheter-based embolectomy procedures that use aspiration, fragmentation, or rheolytic therapy. As of yet, there are currently no guidelines for the use of these therapies and in general they are not advised by the ACCP.⁴³

Vena Caval Interruption

Current guidelines recommend against the routine use of inferior vena cava (IVC) filters for the treatment of VTE. Indications for their placement 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.⁴⁷ The consensus guidelines recently published advise that indications for placing a retrievable IVC filter are the same as for permanent devices.⁴⁶ IVC filter alone is not effective therapy for DVT, and resumption of anticoagulation as soon as possible after placement is recommended.

Direct Thrombin Inhibitors

Three DTIs are currently approved by the FDA for treatment of heparin-induced thrombocytopenia (HIT); however, none have indication for the treatment of VTE. These agents are argatroban (Argatroban), bivalirudin (Angiomax) and lepirudin (Refludan).

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 INR is at least 2.0 for 24 hours. Recent 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.⁴⁷ 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).

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, underlying hypercoagulable states, and patients with an 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 (Box 2). Although the risk of recurrence decreases with longer durations of anticoagulation, clinicians must weigh the risk of bleeding against the risk of new thrombosis.

Current guidelines recommend 3 months of anticoagulation with a VKA targeting an INR of 2 to 3 for patients with a first episode of DVT secondary to a transient cause.⁴⁴ Anticoagulation with a VKA for at least 3 months is recommended for patients with a first episode of proximal idiopathic DVT, although consideration should also be given for indefinite anticoagulation (INR 2.0-3.0) in this situation.⁴³ In patients with unprovoked DVT who prefer less-frequent INR testing after 3 months of conventional intensity VKA therapy (target INR 2.5), lower-intensity VKA (INR 1.5-1.9) treatment with less-frequent testing is recommended over stopping anticoagulation.⁴³ 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 indefinite 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 DVTs.⁴³

Compression Stockings

Damage to the venous valves from DVT can lead to venous hypertension and result in the development of the PTS characterized by edema; skin changes, including increased pigmentation and lipodermatosclerosis; pain; and, in severe cases, venous stasis ulceration. Incidence of PTS is drastically reduced with the use of compression stockings. Current ACCP guidelines recommend their use (at a pressure of 30-40 mm Hg) for 2 years following an acute episode of DVT, and the American College of Physicians and American Academy of Family Physicians recommend use for only 1 year.^{43, 48}

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Summary

The American College of Physicians and the American Academy of Family Physicians have published clinical practice guidelines that summarizes current approaches for treating VTE.⁴⁹

• LMWH should be used over UFH if possible for the initial inpatient treatment of DVT; either UFH or LMWH is acceptable for PE.
• Outpatient treatment of DVT 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 agencies find 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 secondary to 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 efficacious for the long-term treatment of VTE in select 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 prophylactic treatment.² Pulmonary embolism is the most common preventable cause of hospital death in the United States. Without prophylaxis, the incidence of hospital-acquired DVT is 10% to 20% among medical patients and even higher (15%-40%) among surgical patients.⁵⁰ 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.⁵⁰

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.

Screening

Screening asymptomatic patients for DVT is labor intensive and cost ineffective.^51-54 Thus, prophylaxis in at-risk populations remains the most effective means for preventing complications of VTE.⁵⁰

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Considerations in special populations

Calf Vein Thrombosis

Anticoagulation is generally indicated for symptomatic calf DVT or when there is propagation into the popliteal vein or more proximally. Typical duration of treatment is 3 months, with a VKA targeting an INR of 2 to 3 for patients with a first episode of symptomatic calf vein DVT secondary to a transient cause.

Monitoring calf vein thrombosis for propagation into the proximal veins with serial ultrasonography (once or twice weekly for 2-3 weeks) without anticoagulation represents an alternative approach to treatment for patients with a contraindication to anticoagulation.

Superficial Venous Thrombosis

Superficial venous thrombosis often occurs as a complication of an intravenous line, but it can occur spontaneously. Anticoagulation is generally not required due to the lower risk of PE unless the thrombosis propagates into the deep venous system or if the event is spontaneous. Guidelines recommend intermediate doses of UFH or LMWH for at least 4 weeks for spontaneous superficial thrombophlebitis.⁴³

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 there are no contraindications. Thrombolysis should be considered in younger patients with a low risk of bleeding and symptoms of acute onset.⁴³

Phlegmasia Cerulea Dolens

Phlegmasia cerulea dolens is a vascular emergency requiring anticoagulation or, in select cases, thrombolysis or surgical or catheter-based thrombectomy. Fasciotomy may also be required to relieve associated compartment syndromes.

Pregnancy and Venous Thromboembolism

Venous thromboembolism is the leading cause of maternal death. The risk of VTE during pregnancy is increased four-fold; this risk is increased five-fold for 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.

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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 VTE.
• Appropriate prophylaxis remains underused.

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