1. 1
    Current Diagnosis

    • The diagnosis of deep venous thrombosis (DVT) is made with duplex ultrasound imaging and laboratory testing, because history and physical examination are inaccurate in up to half of cases.

    • Duplex ultrasound imaging has become the gold standard for the diagnosis of DVT.

    • Spiral computed tomographic (CT) scanning is preferred as the initial imaging test to establish the diagnosis of pulmonary embolus, replacing ventilation/perfusion scanning (V/Q).

    • Although clinical assessment and D-dimer levels are useful to rule out thrombosis, there is no combination of clinical findings and biomarker testing at this time that can rule in the diagnosis.

  2. 2
    Current Therapy

    • Initial therapy includes low-molecular-weight heparin (LMWH), compression garments, and ambulation once anticoagulation is therapeutic.

    • LMWH should be administered for at least 5 days, during which time an oral anticoagulant (usually warfarin) is begun. Warfarin should be started after heparinization is therapeutic to prevent warfarin-induced skin necrosis. Therapeutic heparinization with LMWH means an appropriate weight-based dose is administered and allowed to circulate. The international normalized ratio (INR) should be therapeutic for 2 consecutive days before stopping LMWH.

    • The goal for warfarin dosing is an INR between 2.0 and 3.0. The new anticoagulants are now favored over warfarin for acute VTE and no cancer.

    • The duration of anticoagulation depends on a number of factors, including the presence of risk factors for thrombosis, the type of thrombosis (idiopathic or provoked), the number of times thrombosis has occurred, venous patency, and the level of D-dimer measured approximately 1 month after stopping warfarin.

    • Significant iliofemoral deep venous thrombosis should be treated with aggressive pharmocomechanical thrombolysis, and pulmonary embolism causing hemodynamic deterioration or right heart strain should be treated with thrombolysis.

  3. 3

    Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE). VTE affects up to 900,000 patients per year and results in 300,000 deaths per year. The incidence has remained constant and may actually be increasing since the 1980s and increases with age. The annual VTE rate among person of European ancestry ranges from 104 to 183 per 100,000 person years.

    Overall VTE incidence may be higher in African-Americans, and lower in Asians and Asian- and Native-Americans. The increasing prevalence of obesity, cancer and surgery account in part for the persistent VTE incidence. Treatment of an acute VTE appears to be associated with incremental direct medical costs of $12,000 to $15,000 (2014 US dollars) with subsequent complications to increase cumulative costs up to $18,000 to $23,000 per incident case. The annual incident cost to the U.S. healthcare system is $7–$10 billion dollars each year.

  4. 4
    Risk Factors

    Risk factors for VTE include acquired and genetic factors. Acquired factors include increasing age, malignancy, surgery, immobilization, trauma, oral contraceptives and hormone replacement therapy, pregnancy and the puerperium, neurologic disease, cardiac disease, obesity, and antiphospholipid antibodies. Genetic factors include antithrombin deficiency, protein C deficiency and protein S deficiency, factor V Leiden, prothrombin 20210A, blood group non-O, abnormalities in fibrinogen and plasminogen, elevated levels of clotting factors (e.g., factors XI, IX, VII, VIII, X, and II), and elevation in plasminogen activator inhibitor-1 (PAI-1). When a patient presents with an idiopathic VTE, family history of thrombosis, recurrent thrombosis, or thrombosis in unusual locations, a work-up for hypercoagulability, including testing for the conditions noted in the previous sentence, may be indicated. Hematologic diseases associated with VTE include heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), disseminated intravascular coagulation (DIC), antiphospholipid antibody syndrome, myeloproliferative disorders, thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS).

  5. 5

    Although Virchow’s triad of stasis, vein injury, and hypercoagulability has defined the events that predispose to DVT formation since the mid-19th century, the understanding today of events that occur at the level of the vein wall and thrombus, including the inflammatory response on thrombogenesis and thrombus resolution, is increasingly becoming appreciated.

  6. 6

    Deep Venous Thrombosis

    The diagnosis of DVT must be made with duplex ultrasound imaging and laboratory testing, because history and physical examination is inaccurate in up to half the cases. Patients often complain of a dull ache or pain in the calf or leg. Wells has classified patients into a scoring system that emphasizes physical presentation, and the most common physical finding is edema. Characteristics that score points in the Wells system include active cancer, paralysis or paresis, recent plaster immobilization of the lower extremity, being recently bedridden for 3 days or more, localized tenderness along the distribution of the deep venous system, swelling of the entire leg, calf swelling that is at least 3 cm larger on the involved side than on the noninvolved side, pitting edema in the symptomatic leg, collateral superficial veins (nonvaricose), and a history of previous DVT. With extensive proximal iliofemoral DVT there may be significant swelling, cyanosis, and dilated superficial collateral veins.

    Massive iliofemoral DVT can result in phlegmasia alba dolens (white swollen leg) or phlegmasia cerulean dolens (blue swollen leg). If phlegmasia is not aggressively treated, it can lead to venous gangrene when the arterial inflow becomes obstructed owing to venous hypertension. Alternatively, arterial emboli or spasm can occur and contribute to the pathophysiology. Venous gangrene is often associated with underlying malignancy and is always preceded by phlegmasia cerulea dolens. Venous gangrene is associated with significant rates of amputation and pulmonary embolism and with mortality.

    Duplex ultrasound imaging has become the gold standard for the diagnosis of DVT. Duplex imaging includes both a B-mode image and Doppler flow pattern. Duplex imaging demonstrates sensitivity and specificity rates greater than 95%. According to the Grade criteria for the strength of medical evidence, duplex ultrasound is given a 1B level of evidence, depending on the pretest probability for DVT. Even at the level of the calf, duplex is an acceptable technique in symptomatic patients. Duplex imaging is painless, requires no contrast, can be repeated, and is safe during pregnancy. Duplex imaging also identifies other causes of a patient’s symptoms. Other tests available for making the diagnosis include magnetic resonance imaging (MRI) (especially good for assessing central pelvic vein and inferior vena cava [IVC] thrombosis) and spiral computed tomographic (CT) scanning (especially with chest imaging during examination for PE).

    A single complete negative duplex scan is accurate enough to withhold anticoagulation with minimal long-term adverse thromboembolic complications. This requires that all venous segments of the leg have been imaged and evaluated. If the duplex scan is indeterminate owing to technical issues or to edema, treatment may be based on factors such as biomarkers, with the duplex repeated in 24 to 72 hours. Combining clinical characteristics with a D-dimer assay can decrease the number of duplex scans performed in the low risk patient. Although clinical characteristics and D-dimer levels are useful to rule out thrombosis, the converse is not true and there is no combination of biomarkers and clinical presentation that can rule in the diagnosis. Work is ongoing to establish new biomarkers based on the inflammatory response to DVT. We have data suggesting that a combination of soluble P-selectin and the Wells score can rule in the diagnosis of DVT, while D-dimer plus Wells is still the best combination to rule out the diagnosis of DVT.

    Conditions that may be confused with DVT include lymphedema, muscle strain, and muscle contusion and systemic problems such as cardiac, renal, or hepatic abnormalities. These systemic problems usually lead to bilateral edema.

    Pulmonary Embolism

    The diagnosis of PE historically has involved ventilation-perfusion (V/Q) scanning and pulmonary angiography. However, the most current techniques include spiral CT scanning and MRI. CT scanning demonstrates excellent specificity and sensitivity. Emboli down to the subsegmental level can be identified. The sensitivity for isolated chest CT imaging is increased when clinical analysis is added and when adding lower extremity imaging to the chest scan. Results from the PIOPED II study demonstrate that if the clinical presentation and spiral CT scan results are concordant, therapies can be safely recommended. However, if clinical presentation and spiral CT scanning are discordant, other confirmatory tests are necessary. For the diagnosis of PE, spiral CT imaging is given a 1A level of evidence. Useful alternate techniques include MRI and VQ imaging.

    Axillary and Subclavian Vein Thrombosis

    Thrombosis of the axillary and subclavian veins accounts for less than 5% of all cases of DVT. However, it may be associated with PE in up to 10% to 15% of cases and can be the source of significant disability. Upper extremity DVT may be primary (approximately 20%), such as from thoracic outlet syndrome, effort thrombosis, or idiopathic; or secondary (approximately 80%), such as from catheter-related, cancer- associated, surgery-related, or pregnancy-related events. Primary axillary and subclavian vein thrombosis results from obstruction of the axillary vein in the thoracic outlet from compression by the subclavius muscle and the costoclavicular space, the Paget-Schrötter syndrome, noted especially in muscular athletes. Secondary axillary and subclavian vein thrombosis results from mediastinal tumors, congestive heart failure, and nephrotic syndrome. Patients with axillary and subclavian vein thrombosis present with arm pain, edema, and cyanosis. Superficial venous distention may be apparent over the arm, forearm, shoulder, and anterior chest wall.

    Upper extremity venous duplex ultrasound is used to make the diagnosis of axillary and subclavian vein thrombosis. Thrombolysis and phlebography are considered as next interventions. If phlebography is performed, it is important that the patient undergo positional phlebography with arm abducted to 120 degrees to confirm extrinsic subclavian vein compression at the thoracic outlet once the vein has been cleared of thrombus. Because a cervical rib may be the cause of such obstruction, chest x-ray should be obtained to exclude its presence (although its incidence is quite low).

  7. 7

    Standard Therapy for Venous Thromboembolism

    The traditional treatment of VTE is systemic anticoagulation, which reduces the risk of PE, extension of thrombosis, and thrombus recurrence. Because the recurrence rate for VTE is higher if anticoagulation is not therapeutic in the first 24 hours, immediate anticoagulation should be undertaken. For PE, this usually means anticoagulation and then testing. For DVT, since duplex imaging is rapidly obtained, usually testing precedes anticoagulation. Recurrent DVT can still occur in up to one third of patients over an 8-year period, even with appropriate anticoagulant therapy.


    Unfractionated heparin or low-molecular-weight heparin (LMWH) is given for 5 days, during which time oral anticoagulation with vitamin K antagonists (usually warfarin) is begun as soon as anticoagulation is therapeutic. It is recommended that the international normalized ratio (INR) be therapeutic for 2 consecutive days before stopping heparin or LMWH.

    LMWH, derived from the lower molecular weight range of standard heparin, has become the standard for initial treatment. LMWH is preferred because it is administered subcutaneously, it requires no monitoring (except in certain circumstances such as renal insufficiency or morbid obesity), and it is associated with a lower bleeding potential. Additionally, LMWH demonstrates less direct thrombin inhibition and more factor Xa inhibition. Compared to standard unfractionated heparin, LMWH has significantly improved bioavailability, less endothelial cell binding and protein binding, and an improved pharmacokinetic profile. The half-life of LMWH is dose independent. LMWH is administered in a weight-based fashion.

    Use of LMWH in outpatient settings usually requires a coordinated effort of multiple health care providers. Certain LMWHs decrease indices of chronic venous insufficiency compared to standard therapy when used over an extended period. This suggests that there are pleotropic effects of the LMWH or that more consistent anticoagulation is accomplished.

    Based on all of the available evidence, LMWH is now preferred over standard unfractionated heparin for the initial treatment of VTE with a level of evidence given 2B (according to the 2012 Chest consensus guidelines).


    Warfarin (Coumadin) should be started after heparinization is therapeutic to prevent warfarin-induced skin necrosis. For standard unfractionated heparin, this requires a therapeutic activated partial thromboplastin time (aPTT); for LMWH, warfarin is administered after an appropriate weight-based dose of LMWH is administered and allowed to circulate. Warfarin causes inhibition of protein C and S before factors II, IX and X, leading to paradoxical hypercoagulability at the initiation of therapy. The goal for warfarin dosing is an INR between 2.0 and 3.0. The duration of anticoagulation depends on a number of factors, including the presence of continuing risk factors for thrombosis, the type of thrombosis (idiopathic or provoked), the number of times thrombosis has occurred, the status of the veins when stopping anticoagulation, and the level of D-dimer measured approximately 1 month after stopping warfarin. One study demonstrated a statistically significant advantage to resuming warfarin over an average 1.4-year follow-up (odds ratio [OR], 4.26; P = 0.02) if the D-dimer is elevated, and a meta-analysis has confirmed this relationship.

    Duration of Treatment

    The recommended duration of anticoagulation after a first episode of provoked VTE is 3 months for both proximal (Grade 1B evidence) and distal thrombi (if symptomatic, Grade 2C evidence). After a second episode of VTE, the usual recommendation is prolonged oral anticoagulation unless the patient is very young at the time of presentation or there are other mitigating factors. VTE recurrence is increased with homozygous factor V Leiden and prothrombin 20210A mutation, protein C or protein S deficiency, antithrombin deficiency, antiphospholipid antibodies, and cancer until resolved. Long-term oral anticoagulation is usually recommended in these situations.

    However, heterozygous factor V Leiden and prothrombin 20210A do not carry the same risk as their homozygous counterparts, and the length of oral anticoagulation is shortened for these conditions.

    Regarding idiopathic DVT, in those with a low bleeding risk, the recommended length of treatment is extended therapy for more than 3 months (Grade 1B evidence). One multicenter trial suggested that low-dose warfarin (INR 1.5–2.0) is superior to placebo, with a 64% risk reduction for recurrent DVT after the completion of an initial 6 months of standard therapy. A second study then suggested that full- dose warfarin (INR 2–3) is superior to low-dose warfarin in these patients without a difference in bleeding. Taken together, criteria for discontinuing anticoagulation, including thrombosis risk, residual thrombus burden, and coagulation system activation, are given a level of evidence of 1B to 2B, depending on the clinical situation. In addition, there is growing evidence that in certain circumstances, such as active cancer, the use of LMWH is superior to LMWH converted to warfarin for long-term treatment, for at least the first 3 months (Grade 2C evidence).


    Bleeding is the most common complication of anticoagulation. With standard heparin, bleeding occurs over the first 5 days in approximately 10% of patients.

    Another complication is heparin-induced thrombocytopenia (HIT), which occurs in 0.6% to 30% of patients. Although historically morbidity and mortality has been high, it has been found that early diagnosis and appropriate treatment have decreased these rates. HIT usually begins 3 to 14 days after heparin is begun, although it can occur earlier if the patient has been exposed to heparin in the past. A heparin-dependent antibody binds to platelets, activates them with the release of procoagulant microparticles leading to an increase in thrombocytopenia, and results in both arterial and venous thrombosis.

    Both bovine and porcine unfractionated heparin and LMWH have been associated with HIT, although the incidence and severity of the thrombosis is less with LMWH. Even small exposures to heparin, such as heparin coating on indwelling catheters, can cause the syndrome.

    The diagnosis should be suspected with a 50% or greater drop in platelet count, when the platelet count falls below 100,000/µL, or when thrombosis occurs during heparin or LMWH therapy.

    The enzyme-linked immunosorbent assay (ELISA) detects the antiheparin antibody in the plasma. This test is highly sensitive but poorly specific. The serotonin release assay is another test that can be used, and this test is more specific but less sensitive than the ELISA test.

    When the diagnosis is made, heparin must be stopped. Warfarin should not be given until an adequate alternative anticoagulant has been established and until the platelet count has normalized. Because LMWHs demonstrate high cross-reactivity with standard heparin antibodies, they cannot be substituted for standard heparin in patients with HIT. Agents that have been FDA approved as alternatives include the direct thrombin inhibitor argatroban. Fondaparinux (Arixtra)1 has also been found effective for treatment of HIT in most cases, but it is not FDA approved for this indication. The use of these alternative agents is given either a 2C and 1C level of evidence.

    Alternative and Future Medical Treatments for Deep Venous Thrombosis and Pulmonary Embolism

    New agents for venous thrombosis treatment include factor Xa inhibitors and direct thrombin inhibitors.

    Fondaparinux (Arixtra) a synthetic pentasaccharide that has an antithrombin sequence identical to heparin, targets factor Xa.

    Fondaparinux has been approved for the treatment of DVT and PE; for thrombosis prophylaxis in patient with total hip replacement, total knee replacement, and hip fracture; in extended prophylaxis in patients with hip fracture; and in patients undergoing abdominal surgery. It is administered subcutaneously and has a 17-hour half-life. Dosage is based on body weight. It exhibits no endothelial or protein binding and does not produce thrombocytopenia. However, no antidote is readily available. In a meta-analysis involving more than 7000 patients, there was more than a 50% risk reduction using fondaparinux as prophylaxis begun 6 hours after surgery compared to LMWH begun 12 to 24 hours after surgery. Major bleeding was increased, but critical bleeding was not. Fondaparinux has also been found effective in prophylaxis of other groups of patients including general medical patients.1 For the treatment of VTE, fondaparinux was found equal to LMWH for DVT, and for PE, it was found equal to standard heparin.

    The new oral anticoagulants are favored over warfarin (Grade 2B) for acute VTE and no cancer. For the new agents, LMWH lead-in is needed for dabigatran and edoxaban, while no lead-in is needed for rivaroxaban and apixaban. Dabigatran targets activated factor II (factor IIa), whereas rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Dabigatran etexilate (Pradaxa) is FDA approved for stroke and systemic embolization prevention in patients with non-valvular atrial fibrillation atrial fibrillation and for treatment and reduction of DVT and PE DVT and PE in patients who have been treated with a parenteral anticoagulant for 5–10 days. Rivaroxaban (Xarelto) is FDA approved for VTE prophylaxis in patients undergoing hip or knee replacements, for stroke and systemic embolization prevention in patients with nonvalvular atrial fibrillation, atrial fibrillation, and for VTE treatment. The Einstein trial evaluated rivaroxaban compared to standard anticoagulation in the treatment of acute DVT. As monotherapy, rivaroxaban was found statistically noninferior to standard therapy, without increased bleeding. Additionally, the Einstein group added a continued treatment group compared to placebo for an additional 6 to 12 months. Extended rivaroxaban showed a significant decrease in recurrent VTE without a significant increase in major bleeding. A similar finding with PE has been noted. Apixaban (Eliquis) is currently FDA approved for the prevention of complications of nonvalvular atrial fibrillation, for prophylaxis of DVT following hip or knee replacement surgery, for the treatment of DVT/PE, and for the reduction in risk of recurrence of DVT/PE. Recently, apixaban as extended treatment of VTE was investigated. After initial treatment, an additional 12 months of apixaban therapy was compared to placebo. This study revealed a significant decrease in the rate of VTE without an increase in bleeding risk. Finally, edoxaban (Savaysa) has been approved for prevention of stroke and non-central-nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation and for treating DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days. Problems with these new agents include the inability at the present time to reliably reverse their anticoagulant effects, the fact that little data are available on bridging of these agents when other procedures need to be performed, and the difficulty with laboratory monitoring. Recently, a monoclonal antibody was FDA approved for the reversal of dabigatran, called idarucizumab (Praxbind), while agents are under development for factorXa inhibitors (andexanet alfa and aripazine).

    Direct oral anticoagulant use has increased from 0.5% in 2010 to 13.4% in 2014.

  8. 8
    Nonpharmacologic Treatments

    The rate and severity of postthrombotic syndrome after proximal DVT can be decreased by approximately 50% by the use of compression stockings. This measure is often forgotten by clinicians. Discussion with the patient on its importance is also critical to ensure good compliance. Additionally, walking with good compression does not increase the risk of PE, whereas it significantly decreases the incidence and severity of the postthrombotic syndrome. The use of strong compression and early ambulation after DVT treatment can significantly reduce the pain and swelling resulting from the DVT. However, a recent multicenter randomized trial has suggested that stockings do not prevent postthrombotic syndrome after a first proximal DVT and for that reason, the most recent ACCP guidelines suggest not using compression stockings to prevent PTS (Grade 2B evidence).

    Aggressive Therapies for Venous Thromboembolism

    For DVT treatment, the goals are to prevent extension or recurrence of DVT, prevent pulmonary embolism, and minimize the late squeal of thrombosis, namely chronic venous insufficiency. Standard anticoagulants accomplish the first two goals but not the third goal.

    The postthrombotic syndrome (venous insufficiency related to venous thrombosis) occurs in up to 30% of patients after DVT and in an even higher percentage of patients with iliofemoral level DVT. The following evidence suggests more aggressive therapies for extensive thrombosis are indicated.

    Experimentally, prolonged contact of the thrombus with the vein wall increases damage. The thrombus initiates an inflammatory response in the vein wall that can lead to vein wall fibrosis and valvular dysfunction. Thus, removing the thrombus should be an excellent solution to decrease this interaction. For example, the longer a thrombus is in contact with a vein valve, the more chance that valve will no longer function.

    Venous thrombectomy has proved superior to anticoagulation over 6 months to 10 years as measured by venous patency and prevention of venous reflux. Catheter-directed thrombolysis has been employed in many nonrandomized studies and in small, randomized trials was more effective than standard therapy. Quality of life was improved with thrombus removal, and results appear to be optimized further by combining catheter-directed thrombolysis with mechanical devices.

    These devices include, but are not limited to, the Trellis balloon occlusion catheter, the Angiojet rheolytic catheter, the EKOS ultrasound accelerated catheter, and new larger bore extraction devices. With these devices, thrombolysis is hastened, the amount of thrombolytic agent is decreased, and bleeding is thus decreased.

    Additionally, the use of venous stents for iliac venous obstruction has been shown to decease the incidence of postthrombotic syndrome and chronic venous insufficiency. To more fully elucidate the role of aggressive therapy in proximal iliofemoral venous thrombosis, a study has been completed by the National Institutes of Health (NIH) to compare catheter-directed pharmacomechanical thrombolysis to standard anticoagulation for significant iliofemoral venous thrombosis. This study, the Attract Trial, will evaluate anatomic, physiologic, and quality-of-life endpoints, with the results currently pending. Data should be available in the spring of 2017.

    For pulmonary embolism, evidence exists that thrombolysis is indicated when there is hemodynamic compromise from the embolism. It is controversial if thrombolysis should be used in situations in which there is no hemodynamic compromise but there is evidence of right heart dysfunction or there are positive biomarkers.

    Inferior Vena Cava Filters

    Traditional indications for the use of IVC filters include failure of anticoagulation, a contraindication to anticoagulation, or a complication of anticoagulation. Protection from pulmonary embolism is greater than 95% using cone-shaped, wire-based permanent filters in the IVC. With the success of these filters, indications have expanded to the presence of free-floating thrombus tails, prophylactic use when the risk for anticoagulation is excessive, when the risk of pulmonary embolism is thought to be high, and to allow the use of perioperative epidural anesthesia.

    IVC filters can be either permanent or optional (retrievable). If a retrievable filter is left, then it becomes a permanent filter; the long- term fate of these filters has yet to be defined adequately in the literature. Most filters are placed in the infrarenal location in the IVC. However, they may be placed in the suprarenal position or in the superior vena cava.

    Indications for suprarenal placement include high-lying thrombi, pregnancy or childbearing age, or previous device failure filled with thrombus. Although some have suggested that sepsis is a contraindication to the use of filters, sepsis has not been found to be a contraindication because the trapped material can be sterilized with intravenous antibiotics.

    Filters may be inserted under x-ray guidance or using ultrasound techniques, either external ultrasound and intravascular ultrasound. Other than two randomized prospective studies on the use of IVC filters as treatment of DVT, evidence for the use of filters is rated at a 2C grade.

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    1  Not FDA approved for this  indication.

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