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Venous thrombosis may occur as a result of the risks as identified in Virchow’s Triad—stasis, endothelial injury, and the hypercoagulable state—or may occur without any known risk factors (unprovoked venous thrombosis). The treatment approach and duration rely upon the patient’s underlying risk factors, extent of thrombus, and/or affected venous segments. We will consider venous thrombosis in the superficial and deep venous systems separately.
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Superficial Thrombophlebitis
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Superficial thrombophlebitis (STP) classically presents as a tender, red, and indurated cord that follows the line of the affected superficial vein. Most often, the GSV is involved. The disease is reported in up to 3% to 11% of the general population, although the annual incidence of disease is not known. Higher rates are seen in malignancy, women over 60 years of age, obesity, thrombophilia, pregnancy or estrogen use, sclerotherapy, autoimmune disease, and those with varicose veins.8,9 Overlap with deep vein thrombosis (DVT) or pulmonary embolism (PE) is reported in up to 25% of patients with STP.10,11 Duplex ultrasonography is recommended to confirm the diagnosis of STP and exclude other causes of the swollen limb (Table 97–1), as well as screen for the presence of a concomitant DVT or extension of the clot into the deep venous system that would warrant treatment with anticoagulation.9,12 First-line management of STP typically includes warm compresses and nonsteroidal anti-inflammatory agents for a period of 7 to 10 days. Most cases of STP are self-limited; however, anticoagulation should be considered in cases that do not respond to conservative management, or if the STP is in close proximity to the deep veins at the sapheno-popliteal (5 cm) or sapheno-femoral junction (10 cm).12,13 Both low-molecular-weight heparin and fondaparinux at prophylactic or therapeutic doses are acceptable therapies for the prevention of DVT or PE in patients deemed to be high risk.12,14 In cases of recurrent STP, testing for thrombophilias, search for systemic diseases (eg, thromboangiitis obliterans, Behçet syndrome), and investigation for underlying malignancy may be appropriate.9
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Presentation, Risk Factors, and Diagnosis
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The classic clinical description of DVT includes unilateral pain, limb swelling, skin erythema, and warmth, with symptoms acute to subacute in onset. However, diagnostic testing is necessary to confirm the diagnosis, as the signs and symptoms of DVT are not reliable and cases may be clinically subtle.15 The use of clinical prediction scores, like the Wells score (Table 97–2), can be helpful in the initial evaluation of a patient with possible DVT to guide healthcare providers in deciding who may warrant additional testing with D-dimer and duplex ultrasound.16,17 If DVT is suspected, an evaluation to confirm and define the extent of DVT should be pursued.17 Findings that support the diagnosis of DVT on duplex ultrasonography include a dilated noncompressible vein resulting from the presence of thrombus, direct visualization of thrombus, as well as altered venous flow dynamics with a lack of respiratory variation resulting from outflow obstruction or a lack of flow augmentation with calf muscle compression, indicating distal obstruction between the calf muscle and ultrasound transducer.18 Catheter-based venography, magnetic resonance (MR), and computed tomographic (CT) venography may have a role in specific situations (eg, evaluation of the pelvic veins, assessing for extrinsic vein compression), although duplex ultrasonography is the standard method for detection of acute DVT in most cases.18,19,20 Challenges with CT venography surround appropriate contrast timing of the target vein and subsequent difficulty in obtaining a diagnostic study; MR venography, on the other hand, shows promise in overcoming the contrast issue seen with computed tomographic, although its use is limited in patients with metallic implants.20 Catheter-based venography is the gold-standard for the direct visualization of venous flow and collaterals, and allows for intraluminal pressure gradient measurements and the use of intravascular ultrasound to detect a significant stenosis within the venous segment.20 The use of catheter-based venography is generally limited to the evaluation of cases with possible stenosis or venous compression, and patients in whom a therapeutic intervention to relieve the obstruction is considered.18,20
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The morbidity and mortality associated with DVT are related to the proximal extent of the thrombus and risk for PE.21 Upper extremity DVT, at the level of the axillary veins or higher, carries risk for PE that is estimated to be as high as ~12%.21,22 Up to 30% of patients with venous thromboembolism (VTE) suffer a mortal event within 30 days,23 most often caused by PE, of which 25% to 30% present with hemodynamic compromise and higher risk of associated sudden death.24 The number of people who experience VTE per year in the United States is not known. However, it is estimated that as many as 900,000 could be affected (1-2 per 100,000).23,25 It is estimated that 60,000 to 100,000 people per year die from VTE in the United States. In general, unprovoked VTE, including DVT and PE, tends to recur with a cumulative incidence of 10% at one year and 30% at 8 years after the first event.26 Risk factors for DVT and PE are many, and may include both intrinsic and extrinsic factors such as sex, ethnicity, inherited or acquired thrombophilia, malignancy, pregnancy, exogenous estrogen hormones, chronic disease with prolonged bedrest, stroke, recent surgery, or injury. Anatomic variants leading to extrinsic vein compression, such as in May-Thurner (Fig. 97–2), are found in up to 20% to 24% of the general population27,28 and may account for the left-sided predominance of DVT described in the lower extremity.29 In the upper extremity, thoracic outlet obstruction (ie, pacemaker implantation, thoracic outlet syndrome, or “Paget-Schroetter” effort thrombosis) and the use of central venous catheters account for most cases.30 Inherited thrombophilias such as factor V Leiden, prothrombin (G20210A) gene mutation, plasminogen-activator-inhibitor 1 (PAI-1) levels or gene abnormal PAI-1 gene polymorphism, antithrombin and protein C/S deficiency are present in approximately 30% of patients presenting with VTE and may confer up to a fivefold increased risk of DVT or PE in their heterozygous state.31,32,33 Despite these rates, routine testing for thrombophilia is not recommended as the presence of an abnormal allele only rarely affects the management of a patient with DVT or PE. Of note, in 25% to 50% of all DVT and PE, no underlying cause or risk factor is identified (unprovoked VTE).25
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In the case of distal calf vein DVT, it is estimated that approximately 15% to 25% will progress to the popliteal vein and/or result in a PE.34,35 For this reason, it is recommended that patients be treated with anticoagulation (especially if symptomatic) or an ultrasound surveillance program (ie, 1-2 week follow-up, especially if there is a significant risk of bleeding on anticoagulation) to evaluate for thrombus propagation if anticoagulation is to be withheld.21,36 Cases in which anticoagulation should be considered over surveillance include severe associated symptoms, extensive thrombus (> 5 cm in length or involving multiple veins), thrombosis in close proximity to the deep veins (5 cm from the sapheno-popliteal junction and 10 cm from the sapheno-femoral junction), lack of identifiable and reversible provoking factors, active cancer, recurrent VTE, and in-patient status.21
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Treatment of DVT involving the popliteal veins, or subclavian-axillary veins in the upper extremity, and more proximal segments is dictated by the presence of reversible or modifiable provoking factors (eg, surgery or exogenous hormone use), the extent of thrombus (DVT versus PE), the patient’s risk of bleeding with anticoagulation therapy, and patient preference. The guidelines for anticoagulation recommend that patients with an identifiable and reversible risk factor be treated with anticoagulation for at least 3 months prior to discontinuation.21,37 In contrast, those without modifiable or identifiable risk factors should be considered for longer treatment duration if the risks of anticoagulation do not outweigh the perceived benefit.21,37 Newer guidelines recognize the direct oral anticoagulants (DOACs) as first-line alternatives to warfarin therapy for the treatment of acute DVT and PE.21,38 The DOACs include one direct thrombin inhibitor, dabigatran, as well as the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban (Table 97–3). There is variability in the recommended dosing regimens, use of heparin versus oral run-in to therapy, cost of drug, and recommended use in the setting of renal insufficiency. All have demonstrated noninferiority in comparison to warfarin for the acute treatment of venous thromboembolic disease.39,40,41,42,43 Apixaban was superior compared to warfarin with regard to rates of major bleeding.42 In patients that have completed the planned duration of anticoagulation and are deemed candidates for extended therapy, low-dose apixaban (2.5 mg twice daily) demonstrated a safety profile equal to placebo and was as effective as full-dose apixaban (5 mg twice daily) for the prevention of recurrent VTE.44
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Advanced therapies including thrombolysis and inferior vena cava (IVC) filter placement may be considered in specific scenarios, although in general these treatments are recommended only on a case-by-case assessment. For patients with a contraindication to anticoagulation, IVC filter placement may be considered for the prevention of PE.21,37,38 However, a recent randomized trial failed to demonstrate any benefit for the use of retrievable IVC filters in patients receiving concomitant treatment with anticoagulation or thrombolysis,45 and the most recent guidelines do not recommend routine use in this setting.21,37,38 Catheter-directed thrombolysis (CDT) and mechanical thrombectomy are typically reserved for patients with occlusive iliofemoral DVT and symptoms ≤ 14 days duration. CDT is used in this setting to correct the outflow obstruction, rapidly relieve patient symptoms, and prevent the complication of the postthrombotic syndrome (PTS).21 However, the data for use of CDT to prevent PTS are limited to small and/or nonrandomized studies.46,47,48,49 A large randomized trial entitled Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) has completed recruitment and is still actively following patients. The results of this trial will help to determine if the PTS can be prevented with more aggressive treatment.50
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Phlegmasia Cerulea Dolens
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Phlegmasia cerulea dolens (PCD) is the most severe manifestation of DVT and occurs when there is near-total venous outflow obstruction of the lower extremity, resulting in limb ischemia.51 PCD is a life- and limb-threatening emergency with up to 50% of cases progressing to venous gangrene following complete occlusion of all deep and superficial veins, as well as microvascular venous collaterals.51 Although literature is scarce, associated mortality of 25% to 40% is reported and up to 15% to 25% of survivors will require amputation.51,52 The clinical triad of PCD includes acute limb pain, massive swelling, and cyanosis, which herald a reversible phase of venous occlusion before gangrene sets in (Fig. 97–3A). Urgent management is imperative at this phase and may include systemic or catheter-directed thrombolysis, mechanical or surgical thrombectomy with or without fasciotomy, or a combination of these modalities in addition to systemic anticoagulation.37,52,53,54 The characteristic changes of gangrene begin distally and move proximal as ischemia progresses (Fig. 97–3B). There is a strong association with malignancy, as well as inherited thrombophilia.
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