A 44-year-old Caucasian woman presented to the emergency department with a 2-week-history of right-leg pain and edema involving the lower thigh to the ankle. One week prior to her emergency room visit, she developed increasing fatigue associated with pleuritic chest pain, exertional dyspnea, and palpitations. Her leg symptoms began within 2 weeks after she was discharged from the hospital after undergoing a 4-day stay for surgery for breast cancer. Her medical history is significant for vasculitis (granulomatosis with polyangiitis/Wegener granulomatosis) and mild iron deficiency anemia. She stopped taking a birth control pill a few weeks prior to surgery. Physical examination demonstrates blood pressure of 138/68 mm Hg, heart rate of 102 bpm, body mass index of 34, regular heart rate and rhythm, and lungs clear to auscultation. The right lower extremity has soft pitting edema with negative Homan sign. There is no cyanosis in the extremities, and distal lower extremity pulses are intact and symmetrical. Acute deep venous thrombosis (DVT) is suspected. The quantitative D-dimer level is 1200 mg/dL, and a venous duplex ultrasound reveals acute DVT involving the common femoral (Figure 53-1), femoral, and popliteal veins.

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  Venous thromboembolic disease, including acute DVT and acute pulmonary embolism (PE), is the third most common cardiovascular disease in the United States.

  
  
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  Approximately two-thirds of all venous thromboembolic events (VTE) are related to hospitalization.

  
  
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  It is estimated that over a million cases of VTE are diagnosed each year in the United States alone.

  
  
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  The absolute risk of DVT or PE in the population (all ages) is estimated at 1% to 3% per year.

  
  
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  The incidence of DVT or PE increases with age. The estimated age-associated incidence of VTE increases approximately from 1 case per 100,000 person-years (1/100,000) in teenagers (estimated absolute risk of 0.001% per year) to 1/100 person-years over the age of 75 (estimated absolute risk of 1% per year).¹

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  Acute DVT or PE is a multifactorial disease. The greater the number of risk factors present, the more likely a patient is to develop acute DVT.

  
  
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  In addition to increasing risk with age, risk factors for DVT or PE can be classified as situational, acquired, or inherited (Table 53-1).^{1,2, and 3}

  
  
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  Situational risk factors can be defined as transient clinical circumstances that increase the risk of VTE while they are present and for a short period (from a few weeks to a few months) after they have resolved.

  
  
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  Acquired risk factors consist of medical conditions that interfere with normal hemostasis or plasma viscosity. Due to their relapsing or remitting clinical course, these conditions tend to increase the risk of VTE periodically. For example, a patient with a vasculitis (such as granulomatosis with polyangiitis) has a significantly increased risk of VTE during a flare of disease activity, but the risk is reduced when the disease is in remission.

  
  
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  Inherited risk factors represent congenital thrombophilias, that is, genetic mutations and polymorphisms that increase the risk of thrombosis by causing specific changes in the delicate balance of normal hemostasis that ultimately result in greater thrombin generation and clinical thrombosis.

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  Rudolph Virchow was a 24-year-old pathologist when he postulated that thrombus formation was influenced by the presence of three conditions (triad): venous stasis, vascular injury, and changes in the blood itself (ie, hypercoagulability of blood). Those conditions, alone or in combination, were invariably present in patients who had DVT diagnosed during autopsy.

  
  
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  Modern understanding of the multifactorial pathophysiology of DVT suggests that, in any given individual, one or several clinical risk factors may cause one or more of the conditions postulated in Virchow triad, hence leading to abnormal thrombus formation. For example, a patient with cancer may have venous stasis (from direct tumor invasion of a vein or by extrinsic venous compression resulting in venous obstruction), vascular injury (by direct invasion of a vein by tumor itself or metastasis), and hypercoagulability due to cancer cell–mediated synthesis of prothrombotic proteins or by increasing plasma tissue factor levels.

  
  
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  Most acute DVT results from thrombus formation that begins in venous valves and/or in calf veins, followed by cranial propagation.⁴

  
  
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  Acute DVT is defined as proximal if it involves the veins at or above the knee level, that is, popliteal, femoral, common femoral, and/or iliac veins. Acute DVT is defined as distal if it involves the calf veins (peroneal, posterior tibial, soleal, gastrocnemius—Figure 53-3).

  
  
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  Approximately 40% to 50% of patients with symptomatic, proximal lower extremity acute DVT without any chest symptoms have evidence of (asymptomatic) PE by pulmonary angiography or ventilation-perfusion scintilography (V/Q scan).⁵

  
  
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  Of all patients with symptomatic acute PE, between 40% and 70% will have a concomitant acute DVT (that may be symptomatic or not) by venous duplex ultrasound of the lower extremities. Two-thirds of these DVTs will be proximal DVTs, while one-third will be isolated calf DVTs.⁶

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  Clinical diagnosis of acute DVT is insensitive and nonspecific.⁵

  
  
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  The severity of signs and symptoms does not necessarily correlate with the extension or location of the acute DVT.

  
  
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  The Homan sign was originally described as calf discomfort elicited by passive dorsiflexion of the ankle of a limb with suspected DVT. It has poor sensitivity (<50%) and unreliable specificity (40%-90%) for the diagnosis of acute DVT.⁷

  
  
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  A concomitant, underlying acute DVT is present in as many as 30% of patients with a clinical diagnosis of acute superficial thrombophlebitis in the lower extremities.

  
  
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  Because clinical diagnosis of DVT is unreliable, objective confirmation by imaging tests is imperative.⁵

  
  
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  Venous duplex ultrasonography is the method of choice for objective diagnosis of an acute femoropopliteal DVT, with sensitivity and specificity greater than 95% to 99%. Duplex implies the use of both gray-scale imaging ultrasound combined with analysis of blood flow by Doppler. The single most accurate and reliable sonographic criterion to diagnose acute DVT is lack of vein compressibility (Figure 53-1, panel B). If a vein is free of thrombus, it will become completely compressible when external pressure is applied directly over the vein (Figure 53-2, panel B). This sonographic maneuver is performed and observed by interrogation of lower extremity veins using gray-scale ultrasound in transverse view (Figure 53-3).

  
  
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  Other imaging methods that can objectively diagnose an acute DVT include computed tomography (CT) with venous-phase contrast, magnetic resonance (MR) venography, and contrast venography.

  
  
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  A normal plasma D-dimer result has a high negative predictive value (approaching 100%) and a very low negative likelihood ratio (approaching zero), thus being a powerful and simple laboratory tool to exclude the diagnosis of acute DVT in patients with a low pretest clinical probability. However, an elevated (positive) D-dimer level has a low positive predictive value and cannot be used to diagnose acute DVT.⁸

  
  
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  Although the clinical diagnosis of acute DVT is not reliable, validated clinical scores can and should be used when evaluating a patient with suspected DVT. These clinical scores usually classify patients into low, moderate, or high pretest clinical probability of DVT.⁹ In patients with a low pretest clinical probability of DVT, a normal quantitative D-dimer essentially rules out acute DVT without the need for imaging studies. However, in patients with a moderate or high pretest clinical probability, an imaging diagnostic test such as duplex ultrasonography should always be used for objective confirmation or exclusion of acute DVT, regardless of D-dimer level.