For the diagnosis of superficial vein thrombophlebitis (SVT), duplex ultrasound is also important.¹³ In a prospective epidemiologic study, including 844 patients with symptomatic SVT, 210 (24.9%) had concomitant DVT at the time of diagnosis of SVT. Of the 600 patients without DVT, over the next 3 months, 58 (10.2%) developed thromboembolic complications, including 3 (0.5%) with PE, 15 (2.8%) with DVT, 18 (3.3%) with extension, and 10 (1.9%) with recurrence of SVT. These events occurred despite the use of anticoagulant treatment. Thus, it is important to perform good duplex imaging in patients diagnosed with SVT.

Finally, in the CALISTO study, fondaparinux (Arixtra) was found effective in limiting a series of endpoints including death, PE, DVT, and extension or recurrence at days 47 and 77 after SVT diagnosis.¹⁴ This was in patients with axial vein SVT of at least 5-cm length with the thrombus at least 3 cm from the saphenofemoral junction (SFJ). Less extensive SVT requires only symptom control with oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, it is important to document the length of the SVT, the location, and the extent of the SVT to the SFJ, when imaging.

Other conditions may be confused with DVT and include lymphedema, muscle strains, and muscle contusion. Iliac vein obstruction may lead to unilateral leg edema (May–Thurner syndrome), while the presence of a cyst behind the knee may produce unilateral lower leg pain and edema. Other causes of leg swelling include systematic problems such as cardiac, renal, or hepatic abnormalities. These systemic problems usually lead to bilateral edema.

Pulmonary Embolism

Testing for PE begins with prior probability estimation for all patients. Two of the most widely known and validated diagnostic scoring systems are the Wells criteria (or modified/dichotomous Wells criteria) and Geneva score.^15–17 They use a combination of physical examination, history, and vital signs to predict the likelihood of PE. D-Dimer testing is used to exclude PE for patients with low prior probability for DVT. D-Dimer testing has no role in diagnosis if prior probability is not low. Use of D-dimer testing in PE diagnosis requires that a high-sensitivity D-dimer assay (such as the advanced turbidimetric method or ELISA) validated at the local institution be used. Patients with both low probability and negative D-dimer require no further investigation as the NPV is 99%.^18,19

The diagnosis of PE has involved ventilation-perfusion (V/Q) scanning and pulmonary angiography. However, newer techniques include spiral computed tomographic scanning and magnetic resonance imaging. The sensitivity of V/Q scanning was defined in PIOPED I at 98%, but specificity was low at 10%.²⁰ By combining clinical factors with V/Q scan, levels of sensitivity and specificity greater than 95% were achieved. With a high-probability V/Q scan, two risk factors positive for PE, the sensitivity was 97%; with one risk factor, 84%; and with no risk factors, 82%. Similarly, with a normal V/Q scan, the chance of PE was essentially 0, irrespective of the risk factor status.²¹ Thus, a normal V/Q scan or a high-probability scan provided good diagnostic information that could be used to base treatment on. However, only a small portion of V/Q scans are in one of these two categories, leaving many patients needing further testing. Because of its invasive nature, pulmonary angiography is used less often today. Pulmonary arteriography is included with acute massive PE, inferior vena cava (IVC) interruption, and when planning interventional therapy, such as thrombolysis or pulmonary embolectomy.

Multidetector helical CTA is the primary imaging modality, although V/Q scanning remains viable (particularly for patients with otherwise normal lungs in whom interpretability of the test is optimal), and a positive lower-extremity color duplex Doppler study in a high-probability patient can establish the diagnosis of VTE without lung imaging. However, the problem with using only lower extremity duplex imaging is that a baseline study in the chest is not obtained for later comparisons. Multidetector scanners have significantly improved the sensitivity and specificity, as well as the positive and negative predictive value of CTA. Recent outcome studies have found the sensitivity and specificity of CTA to be greater than 95%, and a negative CTA carries a 3-month risk of VTE of 1% to 2%. CTA establishes the diagnosis of PE if it is positive in an intermediate- or high-probability patient, or in a low-probability patient with findings of a main-stem or lobar embolus. It excludes the diagnosis of PE in low-probability patients with negative scans. Discordance between prior probability and CTA findings requires further investigation, as well as technically inadequate studies.⁷ Other diagnostic tests may include V/Q imaging or pulmonary angiography.

Outcome studies have found comparable results between pulmonary angiography and CTA; a negative result with either study confers approximately a 1% VTE rate within 6 months. However, because angiography is invasive, it carries a greater risk of complications and mortality. The mortality from angiography has been estimated at 0.5%, while 1% may experience major complications, including arrhythmias, hypotension, bleeding, and nephrotoxicity.²² Without a higher standard to appeal to, one cannot discuss specificity and sensitivity of pulmonary angiography using commonly accepted definitions of these terms. Instead, the accuracy of pulmonary angiography is discussed in terms of interobserver variability in the reading of pulmonary angiograms obtained in the context of large multicenter trials. Studies demonstrate that the larger the embolus, the better the interobserver agreement. For segmental and larger emboli, agreement exceeds 95%. For subsegmental emboli, agreement is considerably less. We do not recommend pulmonary angiography, except in certain circumstances, such as with inadequacy of V/Q imaging or when catheter-directed thrombolysis is recommended.

Recently, the efficacy of magnetic resonance angiography (MRA), magnetic resonance venography (MRV), or the combination of the two in the diagnosis of acute PE has been studied.²³ The gold standard used for comparison was a composite end-point of CTA, CTA-CTV, V/Q scan, lower extremity ultrasonography, D-dimer assay, and clinical assessment. Overall, MRA and MRA-MRV were found to be poor tests for the diagnosis of PE. Approximately 25% of the 371 patients enrolled in a large multicenter study had a technically inadequate MRA, and 48% had either an inadequate MRV or MRA. Considering all patients enrolled, MRA alone identified only 57% of PEs and had a sensitivity of 78% when only patients with adequate studies were considered. The combined MRA-MRV studies had a sensitivity of 92%, but only about half of the patients had technically adequate studies. These poor results are generally felt related to the technical difficulties of MRA in identifying abrupt vessel termination and capturing adequate images of the chest vessels secondary to motion artifact. At this time, MRA-MRV is not generally recommended and only considered in centers with a great deal of experience.

Because of its low sensitivity and specificity, transthoracic or transesophageal echocardiography has limited diagnostic value for PE.²⁴ For critically ill patients too unstable for transport, echocardiography can suggest the diagnosis of PE by showing dilatation of the RV or hypokinesis. Commonly, acute changes in the RV pressure, size, and function are seen, indicating increased RV strain and pulmonary arterial pressures. These changes suggest PE in the absence of alternative diagnoses. Although of limited value in the diagnosis of PE, echocardiography is of great prognostic use in stratifying risk for patients with acute PE. Right ventricular dysfunction or dilatation in acute PE is associated with worse outcomes, including increased mortality rate.

Biomarkers include B-type natriuretic peptide (BNP), released by ventricular myocardial cells in response to wall stretch and volume overload. BNP is a prognostic (not diagnostic) biomarker for PE. BNP levels generally indicate RV strain due to elevated pulmonary vascular resistance in the lungs. If measured early (within 4 hours of admission for PE), elevated BNP levels (>90 pg/mL) demonstrate a sensitivity of 85% and a specificity of 75% in predicting PE-related outcomes. Conversely, normal BNP values in the setting of acute PE carry a 97% to 100% NPV for in-hospital death. Another biomarker is troponin released from damaged myocardial cells. When elevated in acute PE, troponins represent myocyte ischemia and microinfarction due to acute cardiac strain of the right ventricle. Approximately 30% to 50% of patients with large PE will have elevations in troponins I and T that are mild and short-lived. They correlate with worse RV function and a high incidence of complications. Normal troponin T levels have a 97% to 100% NPV for in-hospital death. These two biomarkers are not part of routine algorithms.¹⁹

Axillary/Subclavian Vein Thrombosis

Thrombosis of the axillary/subclavian vein accounts for less than 5% of all cases of acute DVT. However, it may associated with PE in up to 10% to 15% of cases and additionally can also be the source of significant disability.²⁵ Primary axillary/subclavian vein thrombosis results from obstruction of the axillary vein in the thoracic outlet, the so-called Paget–Schroetter syndrome, noted especially in healthy muscular athletic individuals. Such thrombosis may also occur in patients with hypercoagulable states. Secondary axillary/subclavian vein thrombosis results from mediastinal tumors, congestive heart failure, and nephrotic syndrome. Patients with axillary–subclavian venous thrombosis often present with arm pain, edema, and cyanosis. Superficial venous distension may be apparent over the arm, forearm, shoulder, and even the anterior chest wall.

Upper extremity venous duplex ultrasound is used to diagnose suspected axillary–subclavian vein thrombosis. Thrombolysis and phlebography are often considered next. If phlebography is performed, it is important that the patient undergo positional phlebography with arm abduction to 120 degrees to confirm extrinsic subclavian vein compression at the thoracic outlet. Venous compromise is further evidenced by prominent collateral veins. Since a cervical rib may be the cause of such obstruction, chest x-ray film should be obtained to exclude its presence.

STANDARD THERAPY FOR VTE

Treatment

The traditional treatment of VTE is systemic anticoagulation, which reduces the risk of PE, extension of thrombosis, and thrombus recurrence. Immediate anticoagulation should be undertaken as the recurrence rate for VTE is higher if anticoagulation is not therapeutic in the first 24 hours.²⁶ For DVT, since duplex imaging is rapidly obtained, usually testing precedes anticoagulation while for PE, anticoagulation is recommended either simultaneous with or before testing. Recurrent DVT can still occur in up to one third of patients over an 8-year period, even with appropriate anticoagulant therapy.²⁷

Unfractionated heparin or low–molecular-weight heparin (LMWH) is given along with oral anticoagulation with vitamin K antagonists (usually warfarin [Coumadin]). It is recommended that the international normalized ratio (INR) be therapeutic for 2 consecutive days before stopping heparin or LMWH.²⁸ LMWH has become the standard for treatment because it is administered subcutaneously, requires no monitoring (except in certain circumstances, such as renal insufficiency or morbid obesity), and is associated with a decrease in bleeding potential.²⁹ Compared to standard unfractionated heparin, LMWH has significantly improved bioavailability, less endothelial cell binding and protein binding, and improved pharmacokinetics.³⁰ The half-life of LMWH is dose independent and it is administered in a weight-based fashion. LMWHs may decrease indices of chronic venous insufficiency (CVI) compared with standard therapy when used over an extended period. 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).³¹ Warfarin should be started after heparinization is therapeutic to prevent warfarin-induced skin necrosis, as warfarin causes inhibition of protein C and S before factors II, IX, and X, leading to paradoxical hypercoagulability at the initiation of therapy. For standard unfractionated heparin, this requires a therapeutic activated partial thromboplastin time; for LMWH, warfarin is administered after an appropriate weight-based dose of LMWH is administered and allowed to circulate.

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 if the D-dimer assay is elevated over an average 1.4-year follow-up (odds ratio [OR], 4.26), and a meta-analysis has confirmed this relationship.³² The recommended duration of anticoagulation after a first episode of VTE is 3 months.³¹ After a second episode of VTE, the usual recommendation is prolonged warfarin 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. In these situations, long-term warfarin is recommended. 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, the most common of hypercoagulable conditions. Regarding idiopathic DVT, most believe that this diagnosis requires longer than 6 months of anticoagulation, but the actual length is unknown.³³ Taken together, criteria for discontinuing anticoagulation are given a level of evidence of 1B to 2B, depending on the clinical situation.^31,33–37 Recent evidence suggests that the decision to continue anticoagulation indefinitely after a first unprovoked proximal DVT is strengthened if the patient is male, the index event was a PE, and the D-dimer is positive 1 month after stopping anticoagulation.³⁸ 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.

Complications

Bleeding is the most common complication of anticoagulation. With standard heparin, bleeding occurs over the first 5 days in approximately 10% of patients.³⁹ Heparin-induced thrombocytopenia (HIT) occurs in 0.6% to 30% of patients. Although historically morbidity and mortality rates have been high, it has been found that early diagnosis and appropriate treatment have decreased these rates.⁴⁰ HIT usually begins 3 to 14 days after heparin is begun, although it can occur earlier if there has been exposure 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, resulting in thrombosis.⁴¹ Both bovine and porcine unfractionated heparin and LMWH have been associated with HIT, although the incidence and severity of the thrombosis are less with LMWH. Even small exposures to heparin can cause the syndrome. The diagnosis should be suspected with a 50% or greater drop in platelet count, when the platelet count falls less than 100,000/mL or when thrombosis occurs during heparin or LMWH therapy.⁴² A highly sensitive but poorly specific ELISA test detects the antiheparin antibody in the plasma. The serotonin release assay is another test that is more specific but less sensitive.⁴³ When the diagnosis is made, heparin must be stopped and warfarin should not be given until an adequate alternative anticoagulant has been established and the platelet count has normalized. LMWHs cannot be used as substitutes as studies demonstrate high cross-reactivity with standard heparin antibodies. Agents that have been approved by the Food and Drug Administration (FDA) as alternatives include the direct thrombin inhibitor argatroban and bivalirudin (Table 98-1). Fondaparinux has also been found effective for treatment of HIT, but it is not FDA approved for this indication. The use of these alternative agents is given 2C and 1C evidence.⁴⁴

Low–Molecular-Weight Heparin Special Features

When considering once-a-day to twice-a-day LMWH dosing, a meta-analysis of greater than 1,500 patients with VTE demonstrated a nonsignificant difference in the incidence of recurrent thromboembolism, thrombosis size, hemorrhagic events, and mortality.⁴⁵ Twice-a-day dosing may still be more appropriate than once-a-day dosing in patients with marked obesity and patients with cancer.⁴⁶

LMWH has been suggested as a replacement for oral vitamin K antagonists. Rates of recanalization have been reported to be higher in certain venous segments using LMWH and the use of LMWH has been found to lead to improved outcomes in cancer patients compared to standard heparin or LMWH/warfarin therapy when used for 6 months, without differences in rates of major bleeding.⁴⁷ LMWH has also been found to provide better DVT prophylaxis than placebo when used for extended prophylaxis over 4 weeks in patients undergoing abdominal and pelvic cancer surgery.⁴⁸

ALTERNATIVE/FUTURE MEDICAL TREATMENTS FOR DVT

Fondaparinux targets factor Xa with a 17-hour half-life for fondaparinux (Table 98-1). It exhibits no endothelial or protein binding and produces no thrombocytopenia. One disadvantage is the lack of a readily available antidote. Fondaparinux has been tested in the prophylaxis of major orthopedic surgery. In a meta-analysis involving greater than 7,000 patients, there was more than a 50% risk reduction using fondaparinux begun 6 hours after surgery compared with LMWH begun 12 to 24 hours after surgery.⁴⁹ Critical bleeding was not different, although major bleeding was increased. Fondaparinux has also been effective in prophylaxis of general medical patients, abdominal surgery patients, and for extended prophylaxis after hip fracture.^50–52 For DVT treatment, fondaparinux was found equal to LMWH, while for PE, it was found equal to standard heparin.^53,54 Dosage is based on body weight: 5 mg per body weight <50 kg; 7.5 mg per body weight 50 to 100 kg; and 10 mg per body weight >100 kg. Treatment at least for 5 days with concurrent administration of oral anticoagulation is recommended, until the INR is therapeutic at a level of 2 to 3. Fondaparinux has been approved for the treatment of DVT/PE, and for thrombosis prophylaxis in total hip, total knee, and hip-fractured patients, in the extended prophylaxis of hip-fractured patients, and in abdominal surgery patients. A number of novel oral anticoagulants are currently developed or in stages of development to either replace vitamin K antagonists in concert with initial heparin or LMWH, or to replace both heparin/LMWH and vitamin K antagonists totally as monotherapy. These agents hold the promise of not needing monitoring, being safer in terms of bleeding risk than current agents, and being of equal or improved efficacy to established anticoagulants.

2 Dabigatran targets activated factor II (factor IIa), while rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Dabigatran etexilate is FDA approved for stroke and systemic embolization prevention in patients with atrial fibrillation and for treating deep vein thrombosis (DVT) and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days. In trials for VTE, out of six randomized controlled trials (RCTs), dabigatran was noninferior in three trials, superior in two trials, and inferior in one trial. In the Recover trial, which compared dabigatran 150 mg to therapeutic anticoagulation with vitamin K antagonists (INR, 2 to 3) in the treatment of DVT for 6 months, after both were given LMWH or unfractionated heparin for an average of 9 days, dabigatran was noninferior in the 6-month rate of VTE recurrence. In addition, clinically significant bleeding was not significantly different when compared with warfarin.⁵⁵ In addition, in two other VTE trials, dabigatran was found in extended duration treatment to have fewer recurrent VTEs compared with placebo.⁵⁶ Rivaroxaban is FDA approved for VTE prophylaxis in patients undergoing hip or knee replacements, for stroke and systemic embolization prevention in patients with atrial fibrillation, and for VTE treatment. Eight major trials studying VTE and rivaroxaban have been published, with rivaroxaban noninferior in 6 and superior in 2 to standard therapy. The Einstein trial evaluated rivaroxaban compared to standard anticoagulation in the treatment of acute DVT.⁵⁷ As monotherapy, rivaroxaban was found statistically noninferior to standard therapy, without increased bleeding risk. In addition, 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 an increase in major bleeding. A similar finding with PE has been noted.⁵⁸ In a trial for atrial fibrillation, rivaroxaban showed statically less intracranial bleeding or fatal bleeding.

Apixaban is currently FDA approved for the prevention of complications of atrial fibrillation, for prophylaxis of DVT following hip or knee replacement surgery, for the treatment of DVT/PE, and for reduction in the risk of recurrence of DVT/PE. This agent has been evaluated in six studies involving VTE, noninferior in two, superior in three, and a failure in one. In a recent study, Apixaban was given for 7 days of initial treatment for DVT, followed by a lower dose bid versus standard enoxaparin followed by warfarin for 6 months. Apixaban was noninferior to standard therapy with less bleeding.⁵⁹ Apixaban was also studied as extended treatment of VTE.⁶⁰ After a standard duration of treatment, an additional 12 months of apixaban therapy compared to placebo revealed a significant decrease in the rate of VTE without an increase in bleeding. This is the only new oral agent that has revealed superiority to standard therapy without an increase in bleeding in atrial fibrillation patients. Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with VTE, including those with severe PE.⁶¹ Problems with these new agents include the difficulty at the present time to reliably reverse the anticoagulant effects of these drugs with only one approved medication available at the present time, the fact that there is little data available on bridging of these agents when other procedures need to be performed, and the fact that they are nongeneric. Their usefulness for VTE will dramatically improve when adequate reversal agents become clinically available.⁶² The use of P-selectin inhibitors, an area of ongoing research, uses an anti-inflammatory approach to limit thrombus amplification without causing anticoagulation.

NONPHARMACOLOGIC TREATMENTS

Postthrombotic syndrome (PTS) results from loss of competence of the venous valves as a result of DVT or persistent venous obstruction, or a combination of both. It can cause significant morbidity in the form of pain, swelling, skin breakdown, and ulcerations. A Cochrane meta-analysis found a strong effect (OR 0.31) for prevention of PTS using graduated compression stockings beginning within 2 weeks of onset of DVT, with important data highlighted from two open-labeled randomized single-center studies that utilized stockings of 30 to 40 mm Hg for 2 years after DVT.⁶³ From these data, stockings of 30 to 40 mm Hg gradient should be recommended to most patients with DVT, for a minimum of 2 years post-DVT, and longer if they have symptoms of PTS. There is a new study that would suggest that stockings may not prevent PTS after a first proximal DVT.⁶⁴ However, there are a number of specific considerations in this study that will need to be repeated before the recommendation of stockings after DVT is reversed. In addition, ambulation with good compression does not increase the risk of PE, while significantly decreasing the incidence and severity of the PTS.^65,66 Early ambulation has the potential to decrease PTS and improve patients’ quality of life (QOL). Thus, patients should be encouraged to ambulate as part of their post-DVT care recommendations.³¹

IVC Filters

The traditional indications for the use of IVC filters include a complication of anticoagulation, a contraindication to anticoagulation, and failure of anticoagulation. Protection from PE has been greater than 95% using cone-shaped wire-based permanent IVC filters.⁶⁷ Cone-shaped filters have a lower incidence of IVC thrombosis compared with basket-shaped filters, and a recent study between the two filter types was stopped early because of the high rate of IVC thrombosis with the basket-shaped device.⁶⁸ The success achieved with filters has expanded the indications, including free-floating thrombus longer than 5 cm, when bleeding risk with anticoagulation is excessive, when the risk of PE is felt to be very high, and to allow for the use of perioperative epidural anesthesia.^69–71 Filters can be permanent or optional (retrievable). If a retrievable filter is left in to become a permanent filter, the long-term fate of that filter has yet been defined.

Filters are usually placed in an infrarenal location. However, they may also be placed in the suprarenal location or in the superior vena cava. Indications for suprarenal placement include high-lying clot, pregnancy, women of childbearing potential, or a previous device that has failed or become filled with clot. Sepsis is not a contraindication to the use of wire-based filters since the trapped material can be sterilized with antibiotics. Although filters have been placed under x-ray guidance, percutaneous techniques for filter insertion using bedside external ultrasound or intravascular ultrasound are now being recommended. Transabdominal external ultrasound is difficult in the face of morbid obesity, overlying bowel gas, or open abdominal wounds. In these instances, intravascular ultrasound has been found to be more successful.⁷² Other than one randomized prospective study on the use of filters as treatment of DVT (which is not how filters are traditionally used), evidence for the use of filters is given a 2C level of evidence.^73,74

Thrombolytic and Surgical Procedures for Deep VTE

For DVT treatment, the goals are to prevent extension or recurrence of DVT, prevent PE, and minimize the late squeal of thrombosis, namely CVI. Standard anticoagulants accomplish the first two goals but not the third goal. The PTS (venous insufficiency related to venous thrombosis) occurs in up to 30% of patients after DVT and even greater with more proximal iliofemoral DVT.²⁷ Experimentally, prolonged contact of the thrombus with the vein wall increases damage.⁷⁵ The thrombus initiates an inflammatory response in the vein wall that can lead to vein wall fibrosis and valvular dysfunction. Systemic thrombosis in two small series revealed a decrease in the incidence of CVI with streptokinase, as opposed to systemic unfractionated heparin (UFH). However, results depend on complete thrombolysis. Because of this inability to predict complete lysis, combined with its bleeding potential thrombolysis is recommended infrequently. However, urokinase administered directly into venous thrombi has led to an increase in enthusiasm and the publication of a national thrombolysis registry.^76,77 In 473 patients, 287 of whom underwent follow-up, 312 urokinase infusions in 303 limbs were reported. Venous thrombi occurred in the iliofemoral segment in 71% of cases alone, without IVC involvement in 79%, and including the IVC in 21% of cases. Patients had acute disease in approximately two-thirds of cases, 16% had chronic disease, and 19% had combined acute and chronic disease. Approximately 30% had prior DVT. Complete thrombolysis was achieved in 31% and partial lysis in 52% of cases. The mean amount of urokinase used was 7.8 million units, and the mean time of infusion was 53.4 hours. Successful lysis was predicted by acute DVT and no history of prior DVT. Complications included major bleeding necessitating blood products in 11% and minor bleeding in 16%. Mortality rate was 0.4%, intracranial hemorrhage rate was 0.2%, and subdural hemorrhage rate was 0.2%. Total lysis was noted in only 31% of the entire series; however, in patients with acute iliofemoral DVT, no previous symptoms, and the use of the popliteal vein access site, total lysis was more frequent. At 12 months, patency was 79% if lysis was complete, 58% with greater than 50% lysis, and 32% with less than 50% lysis. Absence of valvular reflux was found in 72% of cases with complete lysis, whereas overall valvular reflux was seen in 58% of cases.

Importantly, aggressive therapies have been found to improve QOL. A small randomized study demonstrated that thrombolysis is superior to anticoagulation in patients with iliofemoral DVT.⁷⁸ Results appear to be optimized further by combining catheter-directed thrombolysis with mechanical devices, including the AngioJet^TM rheolytic catheter, and the EKOS MicroSonic^TM accelerated thrombolysis catheter. In addition, new devices (such as the Angiovac) are being developed specifically for large veins. With these devices, thrombolysis is hastened, the amount of thrombolytic agent is decreased, and bleeding is thus decreased. Importantly, a number of small studies have reported a decrease in PTS with catheter-directed thrombolysis for iliofemoral DVT⁷⁹ and long-term results have demonstrated patency rates over 80% with competent valves.⁸⁰ Postthrombotic morbidity correlates with residual thrombus.⁸¹ In addition, the use of venous stents for iliac venous obstruction has been shown to decrease the incidence of PTS and CVI.⁸² To more fully elucidate the role of aggressive therapy in proximal iliofemoral venous thrombosis, a study is in progress, supported by the National Institutes of Health, to compare catheter-directed pharmacomechanical thrombolysis to standard anticoagulation for significant iliofemoral venous thrombosis, with both arms also undergoing ambulation and stocking use. This study, the Attract Trial, will evaluate anatomic, physiologic, and QOL endpoints in addition to vascular laboratory endpoints and a careful evaluation of complications.

Thrombolytic therapy for PE remains controversial. Although agents lyse thrombus effectively, recurrence rates and patient mortality rate were not reduced. However, the original studies were not powered to address this outcome. Results are best if patients are young, the embolus is less than 48 hours old, and the embolus is large. Streptokinase, urokinase, and tissue plasminogen activator have all been used.⁸³ All agents rapidly dissolve clot, but by 7 days, the advantages for all three agents decrease. The benefit of thrombolytic agents for PE thus appears to be greatest in patients who would die as a result of massive PE in the first hour after the PE occurs, which can occur in up to 10% of cases. However, more recent data suggest that thrombolysis may be useful in patients with right ventricular dysfunction without hemodynamic instability and it has been suggested that thrombolysis will improve outcomes if patients have evidence of right-sided heart changes.^84–89 In addition, thrombolysis therapy has been recommended in patients without hypertension who are judged to have a low risk of bleeding.⁷³

Contributions to thrombolytic therapy include:

Absolute

neurosurgery within 3 months

active internal bleeding

recent (<2 months) cerebrovascular accident

intracranial disease

recent gastrointestinal bleeding

Relative Major

recent (<10 days) major surgery, obstetric delivery, or organ biopsy

left-sided heart thrombus

active peptic ulcer or gastrointestinal abnormality

recent major trauma

uncontrolled hypertension (systolic >180 mm Hg; diastolic >110 mm Hg)

recent eye surgery

Relative Minor

minor surgery or trauma

recent cardiopulmonary resuscitation

atrial fibrillation with mitral valve disease

bacterial endocarditis

hemostatic defects (i.e., renal or liver disease)

Venous Thrombectomy

Iliofemoral venous thrombectomy has been advocated to prevent impending venous gangrene. This technique results in mechanical clearing of the venous circulation and may be combined with a temporary arteriovenous fistula. Thrombectomy uses a Fogarty balloon catheter passed from the femoral vein during Valsalva maneuvers. An arteriovenous fistula is constructed so that it can be taken down by nonsurgical techniques. Complete venography in the operating room is recommended, as back-bleeding is unreliable for the assessment of complete thrombus clearance. Thrombosis recurrence rates less than 20% have been reported. The incidence of PE during the first week after thrombectomy is equivalent to the incidence with anticoagulation only. The frequency of clinical success has been reported to be between 42% and 93%.⁹⁰ The largest series of 77 legs with a follow-up period of between 5 and 13 years revealed maintenance of patency, but a steady decline in valvular competence over time.⁹¹

In the only comparative study of iliofemoral venous thrombosis treatment comparing thrombectomy with anticoagulation (31 patients) versus anticoagulation alone (32 patients), iliofemoral vein patency was improved (76% vs. 35%), femoropopliteal patency was improved (52% vs. 26%), and the clinical outcome was better at 6 months (40% asymptomatic vs. 7%).⁹¹ At 10 years, the number of patients available for follow-up had decreased to 13 in the thrombectomy group and 17 in the anticoagulation-alone group. Patency remained improved in the thrombectomy group (83% vs. 41%), and absence of popliteal reflux was found in 78% of the thrombectomy-plus-anticoagulation group compared with 43% of the anticoagulation group alone.

Pulmonary Embolectomy

Surgical approaches for PE are indicated for patients with massive PE with hypotension who require large doses of vasopressors. These are often patients in whom thrombolytic agents have been unsuccessful. Open pulmonary embolectomy is associated with high rates of morbidity and mortality. Today, open pulmonary embolectomy is limited to those who require manual cardiac massage for hypotension or those in whom catheter pulmonary embolectomy fails. However, there may be a more expanded role for pulmonary embolectomy in the future.⁹²

Superficial Thrombophlebitis

SVT is a well-recognized clinical entity, characterized by a painful erythematous and palpable cord-liked structure, usually compromising the lower extremities but capable of affecting any superficial vein in the body. Thrombophlebitis is believed to have a multifactorial etiology, in which Virchow triad of altered blood flow, changes in the vessel wall, and abnormal coagulation are recognized to play a significant role. SVT has been considered a benign disease requiring only conservative management with compression, nonsteroidal anti-inflammatory medications, and lower extremity elevation. Recently SVT, especially above the knee superficial thrombophlebitis, has been reported to coexist with DVT, to propagate to popliteal or femoral level and to even cause PE.^93–97 A medical approach using anticoagulant therapy appears as the treatment of choice when there is above-knee SVT with deep venous system involvement.

The incidence of SVT occurs in approximately 125,000 people in the United States per year.⁹⁸ However, the actual incidence is likely far greater as these statistics may be outdated and many cases go unreported. Approximately 54% to 65% of the reported cases affect females with an average age of 58 years.^93,99 The most frequent predisposing risk factor for SVT is varicose veins, occurring in 62% of patients. Other risk factors include immobilization, trauma, postoperative states, age >60 years, obesity, tobacco use, history of DVT or SVT, pregnancy, puerperium, autoimmune disease, use of oral contraceptives or hormonal replacement therapy, and hypercoagulable state.^93,99,100 Hypercoagulable screening should be considered in patients with ascending or worsening thrombophlebitis despite initial treatment.^101,102 Malignancy has been reported as a risk factor for developing SVT, affecting 13% to 18% of patients.^96,103

The overall recurrence of SVT was described as 18% over 15 months, equally frequent in varicose and nonvaricose phlebitis. Deep venous reflux increases the recurrence rate to 33%, while hypercoagulable states increase the recurrence rate to 42% over the same period of time.¹⁰⁴

The clinical symptoms and signs for SVT are overt. Duplex ultrasound imaging of the affected extremity should be performed to rule out extension of the process into the deep venous system or concomitant DVT.^101,105 Duplex ultrasound shows the extent of the SVT, its relation to the veins connecting with the deep vein system, and the presence of concomitant DVT. In addition, duplex ultrasound allows checking the competence of the valves in the superficial and deep veins.¹⁰⁵

Complete thrombophilia workup is not routinely recommended. However, it may be indicated in selected patients with recurrent primary thrombophlebitis or aggressive thrombophlebitis.¹⁰⁵ Screening for underlying diseases, including malignancy or vasculitis, is performed if signs or symptoms suggest the presence of such a problem.¹⁰⁵

Treatment

Several therapeutic approaches have been proposed for patients with SVT. These include ligation or vein stripping of the affected vein, elastic stockings, NSAIDs to reduce pain and inflammation, and variable doses of unfractionated heparin or LMWH followed by oral anticoagulant therapy. There is no consensus on the optimal treatment of SVT in clinical practice.

The course of treatment for SVT should be tailored accordingly to its location and concomitant DVT if there is any associated infectious process. Thrombus location in trunks of either the great or small saphenous vein (SSV) may have the highest risk of extension into the deep vein system and thus require more aggressive treatment than other locations. The treatment for primary SVT localized in the distal great saphenous vein (GSV) and tributaries veins consists of ambulation, warm soaks, compression, and NSAID agents.^106,107 If the patient presents risk factors for DVT, pharmacologic prophylaxis should be considered seriously.¹⁰⁵

Titon et al. were among the first to compare different approaches on the medical treatment of SVT.¹⁰⁸ In a multicenter study, 117 patients were randomized into 3 groups: fixed dose LMWH calcium nadroparin (n = 38), adjusted-dose LMWH calcium nadroparin (n = 39), and the NSAID naproxen (n = 40) for 6 days. At day 7, heat and redness were significantly less (P < .001) in both groups treated with LMWH compared with those given the NSAID. In addition, at 8 weeks, persistence of symptoms and signs was less frequent in the LMWH-treated groups (P = 0.007). Efficacy did not differ between the fixed and weight-adjusted doses of LMWH.

The management of SVT was further addressed in a randomized, double-blind study describing 427 patients with documented acute symptomatic SVT of the legs.¹⁰⁹ Patients were randomly assigned to receive 40 mg of enoxaparin sodium subcutaneously; 1.5 mg/kg of enoxaparin sodium subcutaneously; oral tenoxicam 20 mg; or placebo, all once daily for 8 to 12 days. LMWH was associated with a lower incidence of SVT extension and/or recurrence, compared with placebo (OR, 0.32; 95% confidence interval [CI], 0.16 to 0.65, and OR 0.33; 95% CI, 0.16 to 0.68, respectively), without major bleeding or HIT. There was no statistical difference with respect to 12-day outcomes between the active treatment groups. However, there was a trend in favor of the LMWH.

The Vesalio Investigator Group compared two regimens of LMWH with each other.¹¹⁰ A total of 164 patients were enrolled and randomized into 2 groups: prophylaxis group (n = 81) and treatment group (n = 83). After completion of 3 months, the cumulative rate of SVT progression and VTE complications did not differ between the prophylactic (8.6%; 95% CI, 3.5 to 17.0) and therapeutic (7.2%; 95% CI, 2.8 to 15.1) groups. No patient in either group developed major bleeding, while one patient in each group developed a clinically asymptomatic HIT. Clinical symptoms improved to a similar extent in both groups, and similar rates of minor extension or recurrent thrombophlebitis were observed during the follow-up period.

Prophylactic dose intravenous (IV) UFH was used as a comparator treatment in two studies.¹¹¹ Relative to elastic stocking alone, prophylactic IV UFH plus elastic stockings was associated with an 86% reduction in SVT extension and/or recurrence (OR 0.14; 95% CI, 0.03 to 0.67). Marchiori et al.¹¹² compared high-dose versus low-dose IV UFH. A nonsignificant 86% reduction in VTE (OR 0.14; 95% CI 0.02 to 1.23) and a 37% (OR 0.63; 95% CI, 0.21 to 1.88) lower rate of SVT extension and/or recurrence were observed in those patients treated with high-dose UFH. There were no episodes of major bleeding and HIT.

LMWH was compared with saphenofemoral disconnection for the treatment of proximal GSV thrombophlebitis in a prospective, randomized clinical study.¹¹³ In this study, 84 consecutive patients diagnosed as presenting SVT alone were divided into 2 groups treated with saphenofemoral disconnection under local anesthesia with a short hospital stay (n = 45) or enoxaparin on an outpatient basis for 4 weeks (n = 39). In all, 30 patients per group completed the study requirements. In the surgical group, 2 patients (6.7%) presented complications of the surgical wound, 1 (3.3%) had SVT recurrence, and 2 (6.7%) had nonfatal PE. In the enoxaparin group, there was no progression of the thrombosis to the deep venous system or PE, there were 2 cases (6.7%) of minor bleeding and 3 (10%) recurrences of SVT. Even when the study found no statistically significant difference between the 2 groups in the treatment of SVT, the LMWH group demonstrated a significant socioeconomic advantage and confirmed the efficacy of LMWH treatment in resolving symptoms and signs and preventing DVT and PE.

Prophylactic-dose LMWH has the advantage over other equally efficacious techniques in resolving symptoms and signs and preventing DVT and PE in cases without concomitant DVT. Patients treated with LMWH do not require hospitalization, present less adverse effects, do not require laboratory monitoring in most situations, and have a low risk of bleeding, and treatment is less expensive if hospitalization is not required. It is generally felt that medical management with anticoagulants versus surgical treatment is somewhat superior for minimizing complications and preventing subsequent DVT and PE development. On the contrary, surgical treatment with ligation at the SFJ combined with stripping (with or without perforator interruption) appears to minimize superficial venous thrombus extension, which ultimately provides improved pain relief.¹¹⁴

Septic thrombophlebitis requires treatment with broad-spectrum IV antibiotics. If rapid resolution of the cellulitis occurs, no treatment beyond a short course of antibiotics and standard treatment for the superficial thrombophlebitis are required. However, if the patient becomes septic, excision of the infected vein is required. With positive blood cultures, an extended course of antibiotics specific for the identified organism is indicated additionally.

The majority of episodes of uncomplicated superficial thrombophlebitis respond to conservative management. However, the recurrence rate for superficial thrombophlebitis has been estimated between 15% and 20%.^115–117 Finally, in the CALISTO study, fondaparinux was found effective in limiting a series of endpoints including death, PE, DVT, and extension or recurrence at days 47 and 77 after SVT diagnosis. This was in patients with axial vein SVT of at least 5-cm length with the thrombus at least 3 cm from the SFJ. Less extensive SVT requires only symptom control with oral or topical NSAIDs.¹⁴

CHRONIC VENOUS DISEASE

Normal Venous Anatomy

The lower extremity venous system is composed of deep, perforating, and superficial veins (Fig. 98-1).¹¹⁸ The common femoral, femoral, deep (profunda) femoral veins in addition to the popliteal and tibial/peroneal veins make up the deep system. The once named “superficial” femoral vein has been changed to simply “femoral vein” to prevent the confusion the term “superficial” implied when treatment of an actual DVT is required. The deep veins lie beneath the investing fascia of the muscles of the leg and thigh (the deep compartment). The saphenous veins have similarly undergone a change in name to the GSV and SSV to standardize the abbreviations that were otherwise extremely confusing. It has also become clear that the GSV and SSV lie within the subcutaneous tissue and surrounded by a separate saphenous compartment. The saphenous nerve lies within the GSV compartment below the knee, which places the nerve at risk of injury during surgery or percutaneous intervention, but if the associated sensory loss occurs, it appears to have little impact on the patient’s QOL in the long term.¹¹⁹ The sural nerve lies in close proximity to the SSV and within its compartment. The superficial veins that lie outside the saphenous compartment, but parallel to the GSV or SSV, are called accessory saphenous veins. The term communicating vein is now reserved for those veins that interconnect with other veins of the same system, and the term perforating vein is reserved for those that penetrate the muscular fascia to connect superficial to deep.¹¹⁸ In the past, perforating veins with rather constant anatomic location have been named after their discoverer (e.g., Crockett’s, Boyd’s perforators), but more descriptive terms designating location are now preferred.¹¹⁸ An excellent international consensus committee description of the standardized venous anatomy nomenclature of the leg and pelvic can be found in an article by Caggiati and colleagues.¹²⁰

The variability of the lower extremity venous system is well known, but only certain anatomic variations are of importance for current surgical practice. The popliteal and femoral veins have variable anatomy and are often duplicated much like the tibial veins. The deep femoral vein often connects directly or through tributaries to the popliteal vein. Although duplication of the GSV has been estimated to be present in up to 50% of patients in some studies, it is becoming evident that duplication of the true GSV lying within the saphenous compartment is much less common.^121,122 The SFJ often has at least four branches in addition to the GSV, but the arrangement and precise location of the branches are quite variable. The most cephalic branch is generally the superficial epigastric vein and is of some importance in new techniques for managing GSV reflux since the vein acts as a landmark for percutaneous interventions and there is a desire to have it remain patent following the procedure. The SSV is rarely duplicated (4%).¹²³ Although the SSV appears to pierce the deep fascia in the upper third of the calf, in reality the membranous layer forming the roof of the SSV compartment is thickened while the muscular fascia disappears, which positions the SSV between the gastrocnemius muscle bellies.¹²³ In only 62% of limbs does the SSV actually end in the popliteal fossa and can well end above the crease of the knee.¹²³ The anatomy of the perforating veins becomes extremely important when considering surgery aimed at preventing reflux into the lower leg. Certainly, removing the GSV will not prevent the impact of perforator reflux if one ignores the fact that the posterior tibial perforators (Cockett perforators of old) connect the posterior accessory GSV with the posterior tibial veins rather than the GSV proper. Similarly, not recognizing that paratibial perforators exist can result in an unsuccessful intervention aimed at preventing calf perforator reflux.¹²⁴

With the exception of foot veins, the valves promote blood flow from superficial to deep and from caudal to cephalad in direction. The valves are made of a fine connective tissue skeleton covered by endothelium and are generally bicuspid, delicate, and extremely strong. The tibial and peroneal veins contain about 7 to 19 valves each. The popliteal vein contains one or two valves and the femoral vein has generally three. About 70% of common femoral veins have a valve located within 1 cm of the inguinal ligament. Twenty-five percent of external iliac and 10% of the internal iliac veins have a valve.¹²⁵ The common iliac vein generally has no valves. The GSV usually has more than six valves (range, 4 to 25) with at least one valve within a few centimeters of the SFJ and the SSV has an average of 7 to 10 valves range, 4 to 13.¹²⁶ Perforating veins and even larger venules have venous valves.¹²⁵

Variable numbers of venous lakes (1 to 18 sinuses) are found in the soleus muscle. These sinuses are valveless, floppy channels linked to small-valved venous channels that prevent reflux to the superficial system. The sinuses empty into the posterior tibial vein in the proximal calf. Within the gastrocnemius muscle, there are interlacing valved venous networks that coalesce to form a pair of venous channels that empty into the popliteal vein. These intramuscular venous chambers store venous blood and are crucial to calf muscle pump function.

The veins of the abdomen and pelvis begin at the inguinal ligament as the external iliac vein that is joined medially by the internal iliac to form the common iliac vein. The internal iliac vein drains the pelvis via connections such as the obturator, gluteal, and internal pudendal veins and their interconnections. To the right of the fifth lumbar vertebrae and aorta, the common iliac veins join to form the IVC. Compression of the left iliac vein by the right common iliac artery can lead to a venous obstructive condition called May-Thurner syndrome. The IVC typically ascends to the right of the aorta and vertebral column terminating in the right atrium. Its direct tributaries are the lumbar veins, the right gonadal vein, the renal veins, the right suprarenal vein, the right inferior phrenic vein, and the hepatic veins. Other named veins generally join one of these tributaries to empty into the IVC. Because of the embryonic evolutions that lead to the “normal” IVC and its branches, variations are common. Duplication of the IVC occurs in 0.2% to 0.3% of cases, transposition or a left-sided IVC can occur in 0.2% to 0.5% of cases, and a retroaortic left renal (1.2% to 2.4%), and circumaortic left renal vein (1.5% to 8.7%) have also been reported.¹²⁷ In the face of IVC occlusion, veins of the chest and abdominal wall, the azygos and hemiazygos systems, and vertebral plexuses may play a prominent role in venous drainage of the lower extremities and abdominal/retroperitoneal cavity.

Normal Venous Physiology

Under conditions of low volume or external pressure, many veins lying within muscle are demonstrated by duplex scanning to collapse in an elliptical configuration consistent with a thin vein wall and the lack of in situ external support.¹²⁸ With muscular relaxation, veins within these compartments change from an elliptical to a circular configuration to accept venous blood being emptied from the superficial system and delivered to the lower extremity by arterial inflow. Compliance is very high; in fact, increasing the venous volume (VV) by over two and one half times results in only a 0- to 15-mm Hg increment rise in pressure.¹²⁹ This allows a significant amount of blood (at least 500 mL in the standing position) to become sequestered in the lower limb without a significant buildup of intraluminal pressure. However, once a vein reaches its full circular shape, further increases in VV result in a proportional increase in intraluminal pressure. The capacitance of the venous system has been met and sustained venous hypertension results in decompensation noted as edema. Normally, modest exercise of the muscles will expel the contained blood volume present in the veins and reset the capacitance of the venous system.

In contrast to intramuscular veins, duplex scanning demonstrates that large axial veins (e.g., femoral, popliteal) collapse in a circular manner. Supported/tethered on all sides by connective tissue, these veins are subject to equal external pressures along the vein wall and expand or collapse in a direct response to changes in volume.¹³⁰ Their compliance mimics that of an artery in that pressure changes are more reflective of volume changes. They are conduit rather than compliance vessels.

The calf muscle and possibly the thigh muscles act as a pump, the “peripheral heart,” which can generate pressures of up to 300 mm Hg during exercise.¹²⁵ Muscle contraction propels the blood toward the heart and lungs via the cephalad conduit veins. The valves in the proximal superficial and deep veins open to allow blood to move forward in response to an increased distal pressure gradient. The perforating vein valves close to prevent venous blood reflux from deep to superficial veins, thereby preventing high pressures generated in the deep system from affecting superficial structures (i.e., skin, soft tissues). In addition, blood moves centrally during exercise by compression of the superficial veins between the deep fascia and skin, but the pressure generated is only 100 to 150 mm Hg.¹²⁵ As the calf muscle relaxes, the flow/pressure gradient falls and proximal vein valve closure prevents reflux (retrograde flow). Arterial blood then slowly fills the venous system; valves in the foot veins and perforating veins open to allow the deep veins to fill from the superficial system replenishing the calf muscle pump venous sinuses.

The vein valve functions in a four-phase cycle: opening, equilibrium, closing, and closed phase. During equilibrium, flow separation occurs at the valve edge, the flow splits into two streams with one of the streams directed into the valve sinus possibly aiding in a self-cleaning step (preventing stasis). When maximally open, the two cusps create about a 35% narrowing of the outflow lumen, which may aid in outflow.¹³¹ Interestingly, the majority of the cycle has the valve in the open position. Valve closure normally occurs within 0.5 to 1.0 second in response to retrograde blood flow and the loss of a pressure/flow gradient.^132,133 Closure time is somewhat dependent on the stimulus to closure and a flow velocity of at least 30 cm/second is required.¹³⁴

An IV catheter placed into a foot vein can measure changes in venous pressure over time and with movement. These measurements reflect normal venous hemodynamics in the distal superficial venous system.¹²⁵ When lying flat, a person’s normal lower extremity IV pressure is about 15 mm Hg, but with standing the pressure rises to reflect the hydrostatic pressure of a column of blood from the heart to the foot catheter most reflective of the patient’s height (generally ±90 mm Hg). A hemodynamic study of venous function involves pressure measurements obtained during controlled exercise. The venous filling time is the time required to arrive at a steady-state pressure after standing. Ten steps (1/second) causes a drop in pressure, and the lowest pressure, called the ambulatory venous pressure (AVP), is generally less than 45 mm Hg. The venous refilling time is the time required, following exercise and standing at rest, to reach the baseline erect pressure. It is normally greater than 20 seconds. This rather simplistic measurement reflects a complex interaction of the venous conduits, the property of the veins, and the action of the peripheral pump.¹³⁵ If one measures the venous pressure in deeper veins and in more central locations, the measurements would be considerably different, but such measurements are not commonly obtained in clinical practice.

Prevalence and Impact

3 Chronic venous disease (CVD) is a common, costly malady in Western countries. If one considers the entire spectrum of the disease, it affects more than 30 million Americans (more than half women).^136,137 Varicose veins are observed in 15% to 25% of the adult population.^138,139 Chronic venous insufficiency is defined as venous pathology that results in advanced clinical symptoms (edema to venous ulceration). Skin changes suggestive of venous disease are noted in 6 to 7 million US citizens, and venous ulcers occur in up to 2% of those with CVI (approximately 500,000 patients).^136,140 Population studies confirm these earlier clinical observations.¹⁴¹ A population-based study that included Duplex imaging and utilized a modified CEAP classification (see later) demonstrated that in San Diego, 5.8% of those studied presented with edema while 6.2% had skin changes and/or prior or active venous ulcers.¹³⁹ The annual cost to treat venous ulcers alone is estimated at $1 billion.^142,143 It is interesting that similar findings are noted throughout Europe.^144–150 Relevant risk factors for varicose veins are advanced age, a positive family history, female gender, multiparity, and obesity when based on epidemiologic studies,^{136,139,144,145,147,148,151} while the risk factors for CVI are advanced age, positive family history, and obesity.^{139,144,148,149}

Pathophysiology and Etiology

Three pathophysiologic states exist: obstruction, valvular insufficiency, and calf muscle pump malfunction. These conditions reflect a failure of one or more of the components of the normal venous system and are not mutually exclusive.

Venous obstruction causes an increased resistance to blood exiting the lower extremity. There are current data to suggest that venous occlusive disease in combination with venous insufficiency is found in 55% of patients with CVI, especially those with the most severe symptoms.¹⁵² Clearly in the past, there existed an underestimation of the importance and prevalence of occlusive disease in the pathophysiology of CVI.^152–154 The hemodynamic result is elevated IV pressure noted clinically as pain especially after exercise.¹⁵² If the deep system is primarily involved, the increased pressure generated with each calf compression may impact the perforating veins resulting in valvular malfunction and lead to venous hypertension in the superficial system and its capillary network. Asymptomatic primary iliac venous compression is quite common with intraluminal (27 ± 5%) and varying degrees of external compression (66% to 88%) observed in the general population.^155–160 Left common iliac vein compression by the right common iliac artery, as well as external iliac vein compression from the internal iliac artery on either side, and variations thereof have been described.^159,161 It has been suggested that the nonthrombotic iliac stenosis is a “permissive lesion” not clinically significant until other components of the lower extremity venous circulation fail.¹⁶² The good results of iliac vein stenting in patients with CVI, even in the presence of untreated reflux, demonstrate the impact that eliminating proximal obstruction has on improving overall venous hemodynamics. In one of the largest experiences treating ileofemoral venous occlusive disease involving nearly 1,000 patients, compression of the common iliac vein was seen in 36%, external iliac vein in 18%, and both sites in 46% of limbs.¹⁶² Of these patients, 53% of limbs had nonthrombotic compressive lesions (absent history of DVT, no venographic or ultrasound findings indicating previous DVT); 40% had postthrombotic obstruction; and 7% had a combined etiology. Furthermore, 20% of the patients were men and 25% of the symptomatic lower limbs were on the right side. Intraluminal webs from repetitive trauma have been reported in 14% to 30% of symptomatic cases of May–Thurner syndrome.¹⁶¹ Extrinsic compression of the iliac and pelvic veins may also be caused by tumor, fibrosis, or infection. Contents of a femoral hernia can crush the femoral vein, as can soft tissue tumors of the thigh. Arterial aneurysms can impinge on the femoral vein. The popliteal vein can be obstructed by a popliteal aneurysm or Baker cyst.¹²⁵ Aplasia of the vein or tumors of the vein wall have been described.^125,163 DVT is associated with inflammation and thrombus resolution resulting in external vein wall scarring with stiffening and thickening, as well as intraluminal recannulation with webs and bands. The venous valves are generally incorporated in the scarring process leading to even more occlusive debri within the lumen. It is a common cause of venous occlusive disease due to its rather high prevalence and can involve any part of the venous system.

Valvular insufficiency occurs throughout the lower extremity venous systems. It has been estimated to account for 85% of symptomatic CVD cases with a 70% incidence of primarily superficial and 30% primarily deep venous insufficiency, but these observations were likely influenced by the lack of recognizing associated occlusive disease as a contributing or sole factor in the symptoms noted.^153,154 Duplex imaging studies suggest that patients with minimal symptoms tend to have isolated superficial reflux while those with edema, skin changes, and past or present ulcers have an increasing presence of perforator and deep disease. In those with more advanced venous disease, reflux alone is observed in 80%, reflux and obstruction in 17%, and only 29% had obstructive disease alone.^164,165 The presence of obstructive and reflux disease had the worse prognosis for the development of skin changes.¹⁶⁶ No matter the clinical stage, the superficial system is most commonly affected (90%) with GSV involvement in 70% to 80%, SSV in 15% to 20%, and nonsaphenous veins in approximately 10%. The deep veins are involved in about 30% and perforator veins in about 20%.^164,165 Those with the most severe sequelae of venous disease have superficial reflux in 74% to 93% with 17% to 54% having only superficial disease.^167–171 In such patients, 50% were noted to have superficial ± perforator disease and less than 10% had isolated deep venous reflux.^170–173 In those patients with venous ulcers, two vein systems were involved in 50% to 70% of patients, and all three systems were involved in 16% to 50% of patients. Since these duplex imaging studies mainly involve imaging of the lower extremity veins, the influence of proximal venous occlusive disease may well be underestimated. Reflux allows the transmission of high venous pressures to the lower leg when standing that cannot be relieved by exercise. Primary valvular insufficiency is rarely a consequence of congenital absence of valves.¹⁷⁴ There are predisposing genetic factors that can lead to primary disease including Klippel–Trenaunay syndrome, FOXC2 gene mutation, desmulin dysregulation, the Ehlers-Danlos syndrome, and a CADASIL gene mutation, to name a few, but these do not reflect the typical patient.^175,176 The muscle cell dilating effect of estrogens may explain the genesis of varicose veins noted in the first trimester of pregnancy. Prolonged exposure to high venous pressures can cause vein dilation as occurs from an arteriovenous fistula or occupations requiring prolonged periods of standing. For our standard patient, venous valve prolapse (elongated, floppy valves) and defects in the vein wall that cause the valve ring to dilate results in malfunctioning valve cusps with retained valve architecture.^177,178 Whether the vein wall changes precede valve insufficiency or the valve insufficiency causes wall distension and wall changes is less clear.^46,175 There are some data to suggest that sustained local venous hypertension might affect the local venous microcirculation. Roughly 50% of deep vein valvular dysfunction occurs secondary to DVT whereas the remainder appears to be of a primary etiology with a 10% to 20% variance, depending on the clinical experience being reported.^{153,179–181} Inflammation and thrombosis associated with DVT tend to cause valve scarring, whether or not recanalization is complete, leaving a damaged valve architecture in contradistinction to primary valvular insufficiency. This classic differentiation between “primary” pathology and “secondary” (or postthrombotic) pathology does not clearly exist when subjected to direct observation of the veins and valves at surgery. In fact, the two conditions can be present in the same patient as noted some 20 years ago.¹⁸² In these cases, the vein wall is thickened and/or fibrotic at the valve station or there is thickening of the valve cusps and/or intima. Pathologic study of 11 such veins demonstrated clear postthrombotic changes in 6, but phlebosclerosis of a nonthrombotic origin in the remaining 5.¹⁸³ Clearly, preservation of a normal valve architecture can be explained if primary reflux and sustained high pressure on the wall are the cause of the changes noted. Another theory is that rapid resolution of acute thrombi, an event known to occur, may have allowed these valves to escape damage or the valve itself may not have been directly involved in the thrombotic process.¹⁸⁴ The fibrotic process involves only the vein wall and the valve cusps become floppy by virtue of a decrease in wall diameter resulting from a thickened, noncompliant vein wall.¹⁸³ The valve remains architecturally intact and can be repaired surgically.

There can be failure of calf muscle pump function. The pump becomes unable to generate the force needed to eject blood from the leg while standing, resulted in sustained venous hypertension. Patients with muscle disuse (e.g., paraplegia, traumatic injury, elderly or bedridden patients) may not have sufficient muscle for effective exercise. Pathologic conditions that result in muscle fibrosis (e.g., muscular dystrophy, multiple sclerosis) can destroy the calf muscle pump. Thrombus and scarring in the gastrocnemius and soleal veins can prevent blood from entering the pump resulting in a deficient volume for ejection with contraction. Calf pump function and ankle range of motion are progressively diminished with increasing severity of CVI.^185–188 Physical conditioning improved both pump function and muscle strength in a small, RCT, demonstrating the influence the pump can have on the lower extremity.¹⁸⁹ With the exception of muscle rehabilitation, very little can be offered to patients with some of these disorders.

Regardless of the etiology, the sequelae of venous hypertension/stasis are changes observed in the lower leg skin and subcutaneous tissues, the end organ. Originally, ischemia from various causes was considered the etiology of the damage noted in the lower leg.¹⁹⁰ More recent observations suggest that far from being simply an ischemic event, the end-organ response to venous hypertension is highly dynamic. The final answer is likely to involve a complex interaction of multiple factors that favor either continued destruction or the ultimate healing of the ulcer. Leukocytes, the extracellular matrix, fibroblasts, and a host of other factors are recruited to heal the early endothelial injury and the more delayed soft tissue injury.¹⁹⁰ In fact, current belief holds that the fundamental basis for CVD and ulceration is inflammation within the venous microcirculation when subjected to increased hydrostatic pressure.¹⁹¹ The soft tissue injury may result in a chronic ulcer that requires growth factors to force the process to healing.¹⁹² Research remains active in this component of venous pathophysiology. An excellent review is available for further information on the current understanding of basis venous pathophysiology.¹⁹³

Clinical Signs and Symptoms

Venous disease presents in many ways. A telangiectasia, spider vein, is a confluence of dilated intradermal venules less than 1 mm in caliber. A reticular vein is a dilated bluish subdermal vein, usually 1 mm to less than 3 mm in diameter and usually tortuous. These venous abnormalities may or may not be accompanied by a larger, more deeply located, pathologic vein.

Hereditary varicose veins usually appear during the second decade of life. If the varicosities are due to a secondary etiology (e.g., thrombosis, trauma), they often present several years after the inciting event. These veins appear alone or in clusters as dilated, often bluish, serpentine, and palpable protrusions of branches of the GSV, SSV, or collateral veins lying beneath the skin within the subcutaneous tissues. Varicose veins generally measure 3 or more millimeters in diameter when measured in the upright position.¹⁹⁴ One finding thought to be an early sign of advanced disease is corona phlebectatica that is a fan-shaped pattern of small intradermal veins located around the ankle or doral foot (also called ankle flare or malleolar flare).^126,194 If the varicose veins observed are the result of proximal disease, such as pelvic reflux or obstruction; the location of the varicosities may be scrotal, perineal, vulvar or posterior/lateral in the lower extremity.¹²⁶

Symptoms may be those associated with any type of CVD and are described as pain, edema, hyperpigmentation, stasis dermatitis or eczema, and/or venous ulcers. These changes often occur in the “gaiter” area just above the medial malleolus. Important perforating veins lay in this area. The observed hyperpigmentation is thought to result from extruded red blood cells that are degraded by macrophages leaving hemosiderin deposits. Less definable but described symptoms of CVD include tingling, burning, muscle cramping, a sensation of throbbing or heaviness, itching, restless or tiredness of the legs, and fatigue.¹⁹⁵ They are more specific indicators of venous disease if made worse with standing and heat and if relieved by rest and leg elevation.

Venous claudication is a pain syndrome experienced when walking and is associated with cyanosis, a sensation of increased swelling, and increased prominence of the superficial veins, which is relieved with rest in combination with elevation of the extremity.^152,196,197 It may be so severe in rare cases that amputation is requested.¹⁹⁸ The most severe form is observed when venous incompetence is associated with obstruction and when the obstructive process is in a more proximal locale.¹⁹⁹

4 Critical to patient management and treatment evaluation is an accurate classification of the disease at any given time. Each patient should be stratified according to the clinical picture, the etiology, the anatomic distribution, and the pathophysiology (CEAP) classification system (Table 98-2).²⁰⁰ This classification system helps the physician define the venous disease so that a focused and appropriate management strategy can be formulated. An extension of the clinical classification system, the Venous Clinical Severity Score, is available to quantify the extent of venous disease and, therefore, to evaluate the patient’s clinical response to treatment (Table 98-3).^201–203 The anatomic and pathophysiologic improvement following a treatment of venous disease can be scored using the Venous Segmental Disease Score.²⁰² While the Venous Disability Score provides some information of what a person can do while afflicted with venous disease.²⁰² QOL surveys have been developed specifically for patients with venous disease to help determine the impact of the disease on the patient’s life and the effect therapy has on the patient’s overall well-being.^{126,193,204–208} Consistent application of these surveys to the pre- and postsurgical outcome of patients has yet to be achieved but is imperative to improve our ability to precisely determine the effect and benefit of a given intervention.

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