Chapter 35: Veins & Lymphatics

VENOUS ANATOMY

Veins of the lower extremity (Figure 35–1) consist of superficial and deep systems joined by venous perforators. The great and small saphenous veins are superficial—veins, the name “saphenous” aptly derived from the Greek word for “manifest, clear,” or “visible.” They contain many valves and show considerable variation in their location and branching points. The great saphenous vein may be duplicated in up to 10% of patients. Typically, it originates from the superficial arch of the foot and is found anterior to the medial malleolus at the ankle. As it ascends in the calf just beneath the superficial fascia, it is joined by two major tributaries: an anterior vein, which crosses the tibia; and a posterior arch vein, which arises posterior to the medial malleolus beside the posterior tibial artery. The great saphenous vein then enters the fossa ovalis in the groin to empty into the deep femoral vein.

The saphenofemoral junction is marked by four or five prominent branches of the great saphenous vein: the superficial circumflex iliac vein, the external pudendal vein, the superficial epigastric vein, and the medial and lateral accessory saphenous veins. Another important anatomic landmark is the relationship of the great saphenous vein to the saphenous branch of the femoral nerve; as it emerges from the popliteal space, the nerve follows a course parallel to the vein. Injury during saphenous vein harvest for bypass produces neuropathic pain or numbness along the medial calf and foot. The small saphenous vein arises from the superficial dorsal venous arch behind the lateral malleolus at the ankle and curves toward the midline of the posterior calf, ascending to join the popliteal vein behind the knee.

Deep veins of the leg parallel the courses of the arteries. Two or three venae comitantes accompany each tibial artery. At the knee, these paired high-capacitance veins merge to form the popliteal vein, which continues proximally as the femoral vein. At the inguinal ligament, the femoral and deep (profunda) femoral veins join medial to the femoral artery to form the common femoral vein. Proximal to the inguinal ligament, the common femoral vein becomes the external iliac vein. In the pelvis, external and internal iliac veins join to form common iliac veins that empty into the inferior vena cava (IVC). The right common iliac vein ascends almost vertically to the IVC while the left common iliac vein takes a more transverse course. For this reason, the left common iliac vein may be compressed between the right common iliac artery and lumbosacral spine, a condition known as May–Thurner syndrome when thrombosis of the left iliac vein occurs.

Muscular sinusoids represent another component of the deep veins of the leg. These thin-walled, nonvalved venous lakes run longitudinally within soleus muscle bellies and then coalesce to join the posterior tibial and peroneal veins. Blood empties from these sinusoids during muscle contraction; inactivity leads to stasis and may contribute to the development of deep venous thrombosis (DVT).

Blood flow is directed from superficial to deep veins of the leg via valved perforating (communicating) veins. Perforators are located below the medial malleolus (inframalleolar perforator), in the medial calf (Cockett perforators), at the level of the adductor canal (Hunterian perforator), and just above (Dodd perforator) and below (Boyd perforator) the knee.

Delicate bicuspid venous valves prevent reflux and direct the flow of blood from the foot and leg toward the heart and generally against gravity. Valves are more numerous in the distal part of the extremity, decrease in number proximally, and are virtually absent in the IVC itself.

The IVC ascends in the abdomen and ends at the right atrium. It lies to the right of the midline, lateral to the aorta, and receives a number of lumbar veins that connect with the vertebral and paravertebral venous plexuses. The IVC and its tributaries are derived in the 6th to 10th week of life from the fusion and obliteration of several paired embryonic veins: the anterior and posterior cardinal veins, the subcardinal veins, the supracardinal veins, and the sacrocardinal veins. Because of this complex embryonic development, anomalies in the venous system are not uncommon. The most common abnormality is a circumaortic left renal vein (1.5%-8.7% incidence), followed by a retroaortic left renal vein (1.2%-3.4% incidence), duplication of the IVC (1%-3% incidence), azygos and hemiazygos continuation of the IVC (0.6%), and left-sided IVC (0.2%-0.5% incidence). An unsuspected retroaortic or circumaortic renal vein can be inadvertently injured during aortic cross-clamping. Most unusual is the congenital absence of the suprarenal IVC, which results from failure of the right subcardinal vein branches to join the veins of the embryologic liver. This ultimately results in the infrarenal segment of the IVC joining the azygos-hemiazygos veins to drain into the superior vena cava. The hepatic veins drain directly into the right atrium in patients with this unusual anomaly.

Veins of the upper extremity are also divided into superficial and deep groups, though direction of flow from superficial to deep is not as distinct as in the lower extremity. Dorsal veins of the hand empty into the cephalic vein (“intern vein”) on the radial aspect and into the basilic vein on the ulnar aspect of the forearm. The cephalic vein ascends lateral to the biceps muscle into the deltopectoral groove, where it passes through the clavipectoral fascia to join the axillary vein. The cephalic vein is useful for arteriovenous fistulas, both at the wrist and in the upper arm, because it is superficial and lateral in the arm, allowing easy access for hemodialysis needles. The basilic vein, which runs medially in the arm to become the axillary vein, is deeper and thicker walled than the cephalic vein. Its many branches make it tedious to harvest, but it can be used for a bypass conduit or for a laterally tunneled upper-arm dialysis fistula (basilic vein transposition). The median cubital vein links the cephalic and basilic veins in the antecubital space.

Paired brachial veins comprise the deep system of veins. They accompany the brachial artery and join the basilic vein as it becomes the axillary vein. The axillary vein continues medially as the subclavian vein, which passes through a tight space anterior to the first rib and anterior scalene muscle and posterior to the clavicle. The subclavian vein and the internal jugular vein join behind the clavicular head to form the brachiocephalic vein, which empties into the superior vena cava.

VENOUS PHYSIOLOGY

Knowledge of lower extremity venous anatomy is essential to understanding the physiology of venous flow. The volume of blood in the lower extremities may increase by one-half liter when an individual moves from a reclining to an erect position (Figure 35–2). Increased blood volume is accommodated by increased venous capacitance, which is regulated by smooth muscle contractility in the vein walls. Erect posture creates a vertical column of blood, exerting a hydrostatic pressure equal to the distance from the toes to the right atrium (about 100-120 mm Hg). The hydrostatic pressure must be overcome to avoid pooling of blood in the legs and to provide venous return to the heart. Several aspects of the venous system make it possible to move blood against the force of gravity. Because the circulation is a closed system, venous return is affected by arterial inflow and by the negative intrathoracic pressure created during inspiration. Functional valves assure unidirectional movement of blood from superficial to deep systems and from the foot back to the heart. Hydrostatic pressure is dissipated by lack of simultaneous opening of the valves. Soleal venous sinusoids are another central component to the system. When the muscle contracts during exercise, blood empties from the sinusoid into the deep veins of the calf and leg. This high-velocity flow siphons blood from deep veins of the foot upward into the calf, analogous to smoke being drawn up a smokestack by wind blowing past the chimney (Venturi effect).

VARICOSE VEINS

General Considerations

Varicose veins are very common, afflicting 10%-20% of the world’s population. Abnormally dilated veins occur in several locations in the body: the spermatic cord (varicocele), esophagus (esophageal varices), and anorectum (hemorrhoids). Varicosities of the legs were described as early as 1550 BC and in the 1600s AD were correlated with trauma, childbearing, and “standing too much before kings.” Modern studies identify female sex, pregnancy, family history, prolonged standing, and a history of phlebitis as risk factors for varicose veins. In the Framingham Study, the highest incidence was found in women between 40 and 49 years of age.

Varicose veins are classified as either primary or secondary. Primary varicose veins are thought to be due to genetic or developmental defects in the vein wall that cause diminished elasticity and valvular incompetence. Most cases of isolated superficial venous insufficiency are primary varicose veins. Secondary varicose veins arise from destruction or dysfunction of valves caused by trauma, DVT, arteriovenous fistula, or nontraumatic proximal venous obstruction (pregnancy, pelvic tumor). When valves of the deep and perforating veins are disrupted, chronic venous stasis changes may accompany superficial varicosities. It is important to recognize that untreated, longstanding venous dysfunction from either primary or secondary varicose veins may cause chronic skin changes that lead to infection, nonhealing venous ulceration, and chronic disability. To define the optimal method of treatment, the etiologic factors and distribution of disease must be clearly identified.

Clinical Findings

The clinical presentation of patients with varicose veins can be quite variable. Many varicose veins are asymptomatic and come to medical attention because of aesthetic concerns. If symptomatic, varicose veins may be associated with localized pain, a burning sensation over the vein, a diffuse ache or “heaviness” in the calf (particularly with prolonged standing), or phlebitis. Mild ankle edema may occur. Symptoms generally improve with leg elevation.

The varicosities appear as dilated, tortuous, elongated veins predominantly on the medial aspect of the lower extremity along the course of the great saphenous vein. Overlying skin changes may be absent even in the presence of extensive large varicosities. Smaller flat, blue-green reticular veins, telangiectasias, and spider veins may accompany varicose veins and are further evidence of venous dysfunction. A cluster of telangiectasias below the inframalleolar perforator is termed a corona phlebectatica paraplantaris. Secondary varicose veins can cause symptoms characteristic of chronic venous insufficiency (CVI), including edema, hyperpigmentation, stasis dermatitis, and even venous ulcerations.

Physical examination begins with inspection of all extremities to determine the distribution and severity of the varicosities. Bimanual circumferential palpation of the thighs and calves is helpful. Palpation of a thrill or auscultation of a bruit indicates the presence of an arteriovenous fistula as a possible etiologic factor. Today, tourniquet tests have been virtually replaced by venous duplex ultrasound imaging, which is now used as the primary method with which to map the location and extent of reflux.

Differential Diagnosis

Ulceration, brawny induration, and hyperpigmentation often indicate accompanying chronic deep venous insufficiency. This is important to recognize because the changes generally do not resolve with saphenous vein stripping alone.

Klippel–Trenaunay syndrome (KTS) must be considered if extensive varicose veins are encountered in a young patient, especially if unilateral and in an atypical distribution (lateral leg). The classic triad of KTS is varicose veins, limb hypertrophy, and a cutaneous birthmark (port wine stain or venous malformation). Because the deep veins are often anomalous or absent, saphenous vein stripping can be hazardous. Standard treatment for patients with KTS is graduated support stockings, and a good program of intermittent leg elevation and exercise. Limited stab avulsion of symptomatic varices after thorough duplex ultrasound vein mapping, and occasional surgery for correction of limb length discrepancy may also be indicated.

Treatment

A. Nonsurgical Treatment

Treatment for both primary and secondary varicose veins initially involves a program directed at management of venous insufficiency, including elastic stocking support, periodic leg elevation, and regular exercise. Prolonged sitting and standing are discouraged. For most patients, knee-high or thigh-high gradient compression stockings of 20-30 mm Hg are sufficient, although some patients require 30-40 mm Hg pressure. The compression stockings are worn all day to diminish venous distention during standing and are removed at night.

B. Surgical Treatment

Traditionally, open surgical approaches have been the mainstay of treatment for saphenous vein disease. The preferred surgical option for saphenous veins remains high ligation with stripping or high ligation alone (Figure 35–3). High ligation and stripping of the saphenous system is performed for patients with an incompetent valve at the saphenofemoral junction and varicosities throughout the length of the great saphenous vein. This was traditionally performed by ligating the saphenofemoral junction and the major proximal saphenous vein branches through a small incision in the groin. Then the saphenous vein was removed to the point of clusters of varicosities. For the small saphenous vein, high ligation alone with short-length phlebectomy with local anesthesia is typically performed to minimize sural nerve injury. Epifascial veins may also be treated in an ambulatory setting, with phlebectomy performed under local anesthesia. Today, most open surgical approaches have been replaced with endovascular techniques (see next paragraph, C). A new treatment strategy called ASVAL (ambulatory selective varices ablation under local anesthesia) embraces the surgical treatment of epifascial veins while sparing the refluxing saphenous vein, minimizing the need to treat the saphenous vein in many cases. Although controversial, under the ­principle of anterograde reflux such that reflux spreads from epifascial to saphenous veins, the treatment of epifascial veins alone is said to correct saphenous reflux. Ongoing research has demonstrated that patients with primary varicose veins or less severe disease have done well with this approach.

C. Endovascular Treatment

In recent years, great advances have been made in endovascular techniques for treatment of varicose veins. Ablation techniques include thermal (radiofrequency and laser) and chemical ablation. Thermal ablation causes treated veins to collapse due to vein wall and lumen fibrosis. Vein reabsorption occurs over the course of several months. Both radiofrequency and laser ablation have been found to be safe and effective in the treatment of incompetent greater saphenous veins (GSVs), and the latest 2011 consensus opinion recommends thermal ablation to surgical or chemical ablation for GSVs. Its use has also been reported in successful treatment of perforator veins, though recent guidelines recommend against selective treatment of incompetent perforating veins in patients with simple varicose veins. However, in patients with “pathologic” perforating veins, subfascial endoscopic perforating vein surgery, ultrasonographically guided sclerotherapy, and thermal ablations remain viable options. Finally, advances have been made in chemical ablation techniques in the form of foam sclerotherapy. Compared to liquid sclerotherapy, foam has increased time of endothelial contact as it expands to fill the vein. Given its ease of use, it is a suggested option for treatment of incompetent saphenous veins and a recommended option along with phlebectomy for treatment of varicose tributaries.

DEEP VEIN THROMBOSIS

General Considerations

DVT and pulmonary embolism (PE) affect up to 900,000 people per year in the United States, and their incidence increases with age. Treatment is estimated to cost billions of dollars per year, not even including expenditures associated with long-term sequelae of this disease.

The Virchow triad (stasis, vascular injury, and hypercoagulability) should be the cornerstone for assessment of risk factors for DVT. In most cases, the cause is multifactorial.

Acquired risk factors include advanced age, cancer, surgery, trauma, immobilization, hormone replacement therapy, oral contraceptive use, pregnancy, neurologic disease, cardiac disease, and antiphospholipid antibodies. Approximately 30%-40% of patients with a new DVT (both upper and lower extremity) have been found to present with malignancy within 5 years. In men, pancreatic and colorectal cancers are most frequently associated with thrombotic risk, while hematological malignancies carry a lower risk. Cancers of the pancreas, ovary, and brain are mostly associated with thrombotic complications. Breast cancer, especially during its chemotherapy treatment, is also a risk factor. Most of these malignancies are associated with increased fibrinogen or thrombocytosis.

Endothelial injury can result from direct trauma (severed vein, venous cannulation, or transvenous pacing) or local irritation secondary to infusion of chemotherapy, previous DVT, or phlebitis. Damaged endothelium leads to platelet aggregation, degranulation, and formation of thrombus as well as vasoconstriction and activation of the coagulation cascade. Thrombin activation from release of tissue factor and diminished fibrinolysis mediated by plasminogen activator inhibitor are intraoperative events that may be related to endothelial disruption.

Hypercoagulable states may also be inherited. Genetic causes include deficiencies of natural coagulation inhibitors (antithrombin III, protein C, protein S), factor V Leiden, prothrombin 20210A gene variant, blood group non-O, elevated homocysteine levels, plasminogen abnormalities, elevated levels of coagulation factors (such as factor VIII), and reduced heparin cofactor II activity. Hematologic disorders associated with DVT include disseminated intravascular coagulation, heparin-induced thrombocytopenia, antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, polycythemia vera, and essential thrombocythemia. Inflammatory bowel disease, systemic lupus erythematosus, and obesity are additionally associated with DVT.

DVT occurs most frequently in the calf veins, though it may arise in the femoral or iliac veins. Thrombi originate in soleal sinusoids or in valve sinuses, where there are flow eddies. Treatment of isolated calf vein thrombosis is controversial, as it is associated with a low risk of PE. However, a 2011 meta-analysis of studies spanning nearly 25 years demonstrated significant reductions both in progression to PE and in proximal thrombus propagation in patients treated with anticoagulation compared to patients who not receiving anticoagulation. While the studies were heterogeneous, the summation of the data indicated no statistical increased risk of bleeding in patients who received anticoagulation compared to the control arms. These observations and the improved safety profile of low-molecular-weight heparin (LMWH) are compelling practitioners to treat isolated calf DVTs aggressively. In the latest 2012 ACCP guidelines, it is recommended that “in patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial anticoagulation” while “in patients with acute isolated distal DVT of the leg and severe symptoms or risk factors for extension, we suggest initial anticoagulation over serial imaging of the deep veins.” The length of anticoagulation recommended is for 3 months.

Clinical Findings

A. Symptoms and Signs

The diagnosis of DVT cannot be made solely on the basis of presenting symptoms and signs, as up to half of patients with acute thromboses have no abnormality detectable in the involved extremity. Homans sign (pain on passive dorsiflexion of the ankle) is nonspecific and positive in only half of cases, and is unreliable. Some patients present with acute PE unaccompanied by leg edema or pain.

Symptomatic patients most often complain of a dull ache or pain in the calf or leg associated with mild edema. With extensive proximal DVT, there can be massive edema, cyanosis, and dilated superficial collateral veins. Low-grade fever and tachycardia occasionally occur. Iliofemoral venous thrombosis can result in phlegmasia. In phlegmasia alba dolens, the leg is pulseless, pale, and cool, which may progress to phlegmasia cerulea dolens, characterized by cyanosis of the limb and a precursor to gangrene.

B. Imaging Studies

Because DVT is difficult to diagnose on the basis of physical signs or symptoms, some objective diagnostic study is required before treatment is started. Historically, the standard for diagnosis was ascending phlebography, accomplished by fluoroscopic imaging during contrast injection into an intravenous line on the dorsum of the foot. The patient stands but is non–weight-bearing on the extremity studied. An abrupt cutoff of the contrast column indicates DVT. The complications of this procedure include risk of contrast allergy, contrast-induced nephropathy, and phlebitis.

Duplex ultrasound is now the best initial test to detect the presence of DVT. It is a noninvasive examination, does not expose the patient to radiation, is easily reproducible, and has specificity and sensitivity of greater than 95%. In this method, the transducer produces a two-dimensional image of the imaged vein and the surrounding tissue. Normally, veins collapse completely when compressed. Vein incompressibility is the primary ultrasonographic diagnostic criterion for acute lower limb DVT. Secondary diagnostic criteria include vein distention, echogenic thrombus within the vein lumen, absence of spectral or color Doppler signal from the vein lumen, and loss of venous flow phasicity and/or loss of response to Valsalva maneuver. Additionally, augmentation is expected in normal, compressible veins. When pressure is applied to the lower extremity distal to the area of evaluation, normally there is increased blood from through the vein with compression. Lack of augmentation is suggestive of an occlusion in the segment of vein between the site of compression and the transducer. It is worth noting that direct thrombus visualization using B-mode imaging is variable depending on the age of the clot: fresh thrombus is anechoic and therefore not visible. Finally, while duplex ultrasound has a high accuracy for proximal DVT, it is less accurate in distal thrombosis and is highly operator dependent. Magnetic resonance venography shows promise as a diagnostic study for this disorder. The sensitivity and specificity of magnetic resonance venography are 100% and 96%, respectively. The injection of gadolinium is useful for determining the age of the thrombus. Advances in magnetic resonance direct thrombus imaging with methemoglobin as an endogenous contrast allows for accurate diagnosis of femoropopliteal DVT with a sensitivity and specificity greater than 100%. This method allows for the paramagnetic properties of methemoglobin to provide a high signal on T1-weighted images against a background of flowing blood and fat. The thrombus may be directly visualized without administration of contrast, making it a viable option for patients with renal insufficiency. CT imaging, especially as part of a PE protocol CT image, may also be a good alternative to establish the diagnosis.

Measurement of D-dimer levels is too nonspecific for use alone and, when combined with a negative risk assessment, may be useful to rule out DVT but not to rule in the diagnosis of DVT. Radiolabeled fibrinogen is too sensitive in the pelvis for use in the acute clinical setting and carries with it a risk of transmission of infectious disease. It is no longer used. Older tests such as impedance plethysmography and venous pressure measurements do not achieve the same accuracy as duplex ultrasound and have been largely abandoned. Recent studies have demonstrated the potential for using soluble P-selectin as a marker for diagnosing DVT. P-selectin is a cell adhesion molecule that is the first upregulated glycoprotein on activated endothelial cells and platelets. As thrombosis and inflammation are interrelated, elevated levels of soluble P-selectin acts as an indicator or biomarker of inflammation. Consequently, a combination of soluble P-selectins with a Wells score has been shown to have a positive predictive value of approximately 90% with a negative predictive value greater than 95% for establishing the diagnosis of DVT.

Differential Diagnosis

A variety of pathologies may mimic the symptoms of DVT. Lymphatic conditions such as adenopathies or lymphangitis can present with lower extremity pain and edema, but without flow on color Doppler images seen with DVTs. Vascular lesions such as hematomas and pseudoaneurysms secondary to catheterization of the common femoral artery may simulate DVTs. These can be differentiated from DVTs under evaluation by gray-scale images showing a delineation of the pseudoaneurysm or hematoma, or by color Doppler imaging which will illustrate the typical “yin-yang” sign of bidirectional flow. Muscular lesions of the thigh such as muscle strains, tears, and contusions may result in pain, stiffness, edema, and a mass. Cellulitis may cause edema, localized pain, and erythema. Unilateral leg swelling can also result from lymphedema, obstruction of the popliteal vein by Baker cyst, or obstruction of the iliac vein by retroperitoneal mass or idiopathic fibrosis. Bilateral leg edema suggests heart, liver, or kidney failure or IVC obstruction by tumor or pregnancy.

Treatment is aimed at reducing the incidence of complications associated with DVT. Short-term complications include recurrent DVT or pulmonary thromboembolism, while long-term complications include the development of varicose veins and chronic venous insufficiency. The primary treatment of DVT is systemic anticoagulation. This reduces the risk of PE and extension of venous thrombosis and also decreases the rate of recurrent DVT by 80%. Systemic anticoagulation does not directly lyse thrombi but stops propagation and allows natural fibrinolysis to occur. Heparin is initiated immediately and dosed to a goal partial thromboplastin time (PTT) of 1.5-2.5 times normal, or, more currently, LMWH, weight-based without monitoring. Achieving therapeutic heparinization within the first 24 hours after diagnosis is shown to reduce the rate of recurrent DVT.

Warfarin is started after therapeutic heparinization. The two therapies should overlap to diminish the possibility of a hypercoagulable state, which can occur during the first few days of warfarin administration, because warfarin also inhibits the synthesis of natural anticoagulant proteins C and S. For both acute lower extremity DVT and acute PE, guidelines recommend starting warfarin the same day as the start of parenteral anticoagulation over delayed initiation, with a continuation of parenteral anticoagulation for a minimum of 5 days until the INR is greater than 2.0 for more than 24 hours. Specifically, in patients with a PE or proximal DVT of the leg provoked by surgery, the recommended treatment is 3 months compared to a longer or shorter time period. Three months of anticoagulation is similarly recommended in patients with (i) PE/proximal DVT of the leg provoked by a nonsurgical transient risk factor, (ii) in patients with PE/an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor. In patients who have had an unprovoked PE or DVT of the proximal or distal leg, the recommended treatment is a minimum of 3 months’ treatment followed by reevaluation of risk-benefit ratio of extended therapy. After a second episode of DVT, the usual recommendation is prolonged or lifelong warfarin in patients with a low or moderate bleeding risk. In patients with a high bleeding risk, the guidelines recommend 3 months of anticoagulation over extended therapy. The risk for recurrent venous thrombosis is increased markedly in the presence of homozygous factor V Leiden mutations, antiphospholipid antibody, antithrombin III, and protein C or protein S deficiencies, so lifelong anticoagulation is usually recommended for these conditions as well.

LMWH has been shown to be as safe and effective as standard unfractionated heparin (UFH) in the treatment of DVT. It is administered once or twice daily by subcutaneous injection. LMWH does not require monitoring of its anticoagulant effect because of its predictable dose-response relationship, and this feature of the drug has made feasible the outpatient treatment of DVT. Standard UFH inhibits t­hrombin because it is large enough to make a three-way complex between thrombin, antithrombin, and itself. LMWHs are much smaller than standard heparin molecules and do not inhibit thrombin; their main therapeutic effect comes from inhibition of factor Xa activity. In patients with acute DVT of the leg or acute PE, the most recent 2012 ACCP guidelines suggest LMWH over both IV and SC forms of UFH. LMWH is suggested over vitamin K antagonist therapy for patients with PE or DVT of the leg and cancer. The advantages of LMWHs over standard heparin preparations include a lower risk of bleeding complications and thrombocytopenia, a lower risk of heparin-induced thrombocytopenia, lower recurrence of VTE, decreased mortality, less interference with proteins C and S, less complement activation, and a lower risk of osteoporosis. Moreover, recent randomized trials have shown regression of thrombus with LMWH. A disadvantage worth noting is that LMWH accumulates in patients with renal failure.

Recent studies evaluating specific factor Xa inhibitors and direct thrombin inhibitors have demonstrated significant promise. Fondaparinux is a synthetic pentasaccharide which binds to antithrombin and catalyzes the inhibition of factor Xa. It has more specific anti-Xa activity than low molecular weight heparin (LMWH), and has a longer half-life than LMWH. It is rapidly and almost completely bioavailable after subcutaneous injection, and does not require coagulation monitoring. However, due to its dependence on renal clearance, its use is contraindicated in patients with renal insufficiency. For the treatment of VTE, fondaparinux is administered at a fixed dose of 7.5 mg for patients weighing 50-100 kg, with the dose adjusted to 5 mg for patients weighing less than 50 kg and 10 mg for those weighing more than 100 kg. In orthopedic patients undergoing total hip or knee arthroplasty or hip fracture surgery (HFS), fondaparinux is among one of the recommended agents for use as prophylaxis by the current 2012 ACCP guidelines (grade 1C). In patients with acute VTE, ACCP guidelines recommend initial treatment with parenteral anticoagulation agents—among those—subcutaneous fondaparinux (grade 1B). For the treatment of VTE, fondaparinux was found to be equal to LMWH for treating DVT, and for PE, it was found as effective as UFH.

Dabigatran etexilate (Pradaxa) is an oral direct thrombin inhibitor. It has been approved for prophylaxis in total hip replacement and total knee replacement in Western Europe and Canada. It demonstrates a low risk for bleeding, offers fixed oral dosing without coagulation monitoring, and does not cause an increase in liver enzymes. When tested against LMWH given twice daily in DVT prophylaxis, it failed to meet the noninferiority target that was achieved when compared with LMWH once daily. Dabigatran was recently found to be as effective as warfarin for the treatment of DVT, and has now been approved by the FDA as an oral anticoagulant for treatment of nonvalvular atrial fibrillation. Another oral agent, Rivaroxaban, has been studied as monotherapy for treatment of DVT and was found noninferior to standard therapy in the primary endpoint of symptomatic recurrent DVT and nonfatal or fatal PE, without any increase in bleeding. Finally, Apixaban is yet awaiting FDA approval, but it has been shown to be superior to warfarin in the treatment of atrial fibrillation in patients with that diagnosis and one additional risk factor for stroke.

The prevention of CVI after DVT can be divided into those measures that are useful with traditional anticoagulant treatment of DVT and measures that involve more aggressive interventions to lyse thrombus. Certain LMWHs decrease indices of CVI compared to standard therapy when used over an extended period of time. Associated with this traditional therapy, the rate and severity of the postthrombotic syndrome (PTS) after proximal DVT can be decreased by approximately 50% by the use of surgical compression stockings and ambulation without increasing the risk of PE.

The clinical outcome after DVT can be thought of as resulting in either valvular reflux, persistent venous obstruction, or their combination. Patients with both obstruction and valvular reflux often have the most severe postthrombotic symptoms. In order to limit these consequences, thrombus removal should be the best solution. The longer a thrombus is in contact with a vein valve, the more likely the valve will no longer function. Additionally, the thrombus initiates an inflammatory response in the vein wall, which may lead to vein wall and valve dysfunction. The most recent guidelines recommend early thrombus removal in patients with limb-threatening venous thrombosis (grade 1A), though recommend that patients with isolated femoropopliteal DVTs to be managed with only conventional anticoagulation therapy (grade 1C).

Techniques for early thrombus removal include catheter-directed thrombolytic therapy and open thrombectomy. In the treatment of acute iliofemoral DVTs, a systematic review and meta-analysis by Casey and colleagues reports that thrombectomy results in significantly decreased risk of developing PTS, venous reflux, and a trend for reduced venous obstruction when compared to systemic anticoagulation. Catheter-directed thrombolysis yielded similar results when compared to systemic anticoagulation, though there were insufficient data to directly compare outcomes of catheter-directed thrombolysis to thrombectomy. Following either therapy, it is currently recommended that patients wear knee-high compression stockings (30-40 mm Hg) for at least 2 years following the procedure.

Prevention of VTE

Surgery increases the risk of DVT 21-fold. This disorder is a reported complication for approximately 20%-25% of patients admitted for a general surgical procedure, 20%-30% of those undergoing an elective neurosurgical procedure, and 50%-60% of those undergoing hip or knee arthroplasty. These statistics emphasize the need for routine DVT prophylaxis in the surgical patient. The most commonly used measures are elastic stockings, pneumatic sequential compression devices, low-dose UFH (5000 units given by subcutaneous injection), or LMWH given at a prophylactic dose subcutaneously (either once or twice daily).

For general surgical patients, the incidence of DVT is high without prophylaxis, and the risk of PE is 1.6%, 0.9% fatal. Patients have been categorized into levels of risk in the current Chest guidelines based on their risk scoring via the Rogers or Caprini scoring system, placing a very low risk for VTE patient at more than 0.5%, low risk at approximately 1.5%, moderate risk at approximately 3%, and high risk at approximately 6%. In general surgery patients at very low risk for VTE, the recommended prophylaxis is simply early ambulation, with no pharmacologic or mechanical prophylaxis recommended. For patients at low risk, the guidelines suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC). Patients at moderate risk of VTE who are not at high risk for major bleeding complications are suggested LMWH, low-dose unfractionated heparin (LDUH), or mechanical prophylaxis. In those at moderate risk of VTE but at high risk for bleeding, the guidelines suggest mechanical prophylaxis. For high risk VTE patients who are not at high risk for major bleeding, the recommendation is pharmacologic prophylaxis with LMWH or LDUH, with the additional suggestion of mechanical prophylaxis. In the special case of high VTE risk patients with cancer who are not high risk for bleeding complications, the guidelines recommend IPC with LMWH for extended-duration pharmacologic prophylaxis (4 weeks) over a shorter duration.

For orthopedic patients having undergone major surgery including hip fracture surgery (HFS), total hip arthroplasty (THA), or total knee arthroplasty (TKA), an evaluation of the extended postoperative VTE risk (postoperative days 0-35) comparing no prophylaxis with LMWH found the total symptomatic VTE rate decreased from 4.3% to 1.8%, a greater than 60% reduction. These values represent a decrease in rates of PE from 1.5% to 0.55% and a decrease in rates of DVT from 2.8% to 1.25%. Therefore, the current guidelines suggest extending thromboprophylaxis for up to 35 days postoperatively (grade 2B). For patients undergoing THA or TKA, the use of LMWH is suggested over fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH, adjusted-dose VKA, or aspirin. In patients undergoing HFS, LMWH is also the suggested agent, regardless of concomitant use of mechanical prophylaxis. If started preoperatively, LMWH is suggested to be administered ≥12 hours prior to surgery. In patients with increased risk of bleeding or contraindications to both pharmacologic and mechanical thromboprophylaxis, the guidelines suggest against using an IVC filter over no thromboprophylaxis.

For trauma patients, evidence is lacking, and randomized studies are needed. Trauma risk factors include lower extremity or pelvic fractures, surgical procedures, advanced age, femoral vein lines or major venous repairs, prolonged immobility, spinal cord injury, and prolonged duration of hospital stay. In major trauma patients, the guidelines suggest the use of LDUH, LMWH, or mechanical prophylaxis. For these patients at high risk for VTE, such as those with acute spinal cord injury or traumatic brain injury, mechanical prophylaxis is suggested in addition to pharmacologic prophylaxis. Because venous compression ultrasound detection and subsequent treatment of asymptomatic DVT in this population does not reduce the risk of PE or fatal PE, the guidelines do not suggest periodic surveillance with this modality. IVC filters are recommended in patients when anticoagulation is contraindicated, but are not suggested for use as primary prevention.

In neurosurgery, DVT and PE occur equivalent to rates in general surgery patients, and risk factors include intracranial surgery, prolonged surgery, malignant tumors, the presence of leg weakness, and increased age. The recommendations differ between craniotomy and spine surgery patients. In craniotomy patients, the suggested prophylaxis is mechanical or pharmacologic or no prophylaxis. However, in those craniotomy patients who are at very high risk for VTE, such as those with malignant disease, the guidelines suggest pharmacologic prophylaxis in addition to mechanical prophylaxis when it is safe to do so. For spinal surgery patients, mechanical prophylaxis is suggested over no prophylaxis, UFH, or LMWH. Similar to their counterparts, spinal surgery patients at very high risk for VTE are suggested to have both pharmacologic and mechanical prophylaxis when medically safe.

AXILLARY-SUBCLAVIAN VENOUS THROMBOSIS

General Considerations

Thrombosis of the axillary or subclavian vein is a relatively uncommon event, accounting for less than 5% of all cases of DVT. Only 12% result in clinically apparent pulmonary thromboembolism, but the incidence is higher if all patients undergo diagnostic testing. Besides PE, the most common consequence of axillary-subclavian vein thrombosis is chronic edema and resultant disability. The effects of post-thrombotic syndrome (PTS) and recurrent thrombosis are not uncommon.

There are two major etiologies. Primary axillary-­subclavian thrombosis, also known as Paget–Schroetter syndrome or “effort thrombosis,” occurs as a result of intermittent transient obstruction of the vein in the costoclavicular space during repetitive or strenuous activities involving the upper extremity (Figure 35–4). This condition was first described in independent reports by Paget and von Schroetter in the late 19th century. During strenuous repetitive movements of the upper extremity, the subclavian vein is compressed between the first rib and the anterior scalene muscle posteriorly and the clavicle—with underlying subclavius muscle and fibrous costocoracoid ligament—anteriorly. In many cases, the costoclavicular ligament congenitally inserts more laterally than normal, subjecting the anatomically tight space to further compression of the subclavian vein. Primary subclavian vein thrombosis can also occur in patients with hypercoagulable states such as antiphospholipid antibody syndrome or factor V Leiden mutation. Secondary subclavian vein thrombosis, which is increasing in incidence, results from venous injury by indwelling central venous catheters, external trauma, or pacemaker wires. These patients are less likely to be symptomatic than patients with primary subclavian vein thrombosis.

Clinical Findings

A. Symptoms and Signs

Primary axillary-subclavian vein thrombosis usually occurs in healthy young athletes and people who perform repetitive activities that involve hyperabduction of the upper extremities. Most patients present with edema of the affected extremity, diffuse aching pain, and cyanosis of the upper extremity. As venous collaterals develop, dilated veins appear in the chest wall and shoulder region. In less pronounced presentations, patients become symptomatic only when their affected extremity is positioned in a way that predisposes it to vascular occlusion.

Paget–Schroetter syndrome may also be accompanied by symptoms of neurogenic thoracic outlet syndrome, often causing tingling, numbness, and pain in the hand and arm, sometimes in an ulna distribution indicating compression of the C-8/T-1 roots of the brachial plexus between hypertrophied or anomalous anterior and middle scalene muscles.

B. Imaging Studies

Upper extremity venous duplex ultrasound is a sensitive and reliable modality to diagnose axillary-subclavian vein thrombosis.

Magnetic resonance venography has demonstrated promise with greater than 97% sensitivity and specificity for diagnosis, but its cost and limited availability reduce its wide-spread use. While computed tomographic venography is widely available, its use exposes the patient to contrast dye. Venography, while invasive, remains the common next step in diagnosis, with a positive venogram indicating subclavian vein compression with the appearance of prominent collateral veins. Obtaining these images allows delivery of catheter-directed thrombolysis and allows for further planning of thoracic outlet decompression surgery.

Chest x-ray should be obtained on all patients to exclude the presence of cervical rib, which can also contribute to compression of the subclavian vein.

Treatment

For patients with secondary axillo-subclavian thrombosis, any indwelling central venous lines or pacemaker wires in the thrombosed vein should be removed if possible. If not contraindicated, anticoagulation should be considered as well as arm elevation and pain control.

Patients who have primary venous thrombosis secondary to thoracic outlet compression should be considered for decompression because, if left untreated, the patients have a 35%-65% risk of PTS characterized by recurrent episodes of pain, swelling, and chronic venous insufficiency (CVI) secondary to venous hypertension and valvular damage.

The current standard of care is catheter-directed thrombolysis followed by surgical decompression of the thoracic outlet in the majority of cases. Catheter-directed thrombolysis is beneficial to patients presenting early, and offers therapeutic value without the higher rates of bleeding complications seen in systemic fibrinolysis. As the success of thrombolysis decreases as time from onset of symptoms increases, the early initiation of treatment is paramount. Some have advocated a treatment window of two weeks, as there is progressive fibrosis of the vein and risk of extension of the thrombus distally into the arm with decreased chance of recovery. In patients who are more than six weeks from initial presentation of symptoms, thrombolytic agents were generally ineffective in completely removing the clot. Inflow is typically inadequate by the time patients present with chronic obstruction.

Because the etiology of venous thoracic outlet syndrome is compression of the vein between the first rib–anterior scalene muscle origin and the clavicle, surgery consists of anterior scalenectomy, first rib resection, and venolysis (release of the vein from any externally constricting scar). It is particularly important to resect the entire medial portion of the rib to the sternal junction when an anterior, or subclavicular, approach is used. Some prefer this to the transaxillary approach, as the transaxillary approach prevents full resection of the medial rib, and allows for intact subclavius tendons and costoclavicular ligaments, resulting in kinking of the vein on any of these residual structures. However, others find that the transaxillary dissection minimizes the exposure of the neurovascular structures, minimizing their injury. In either case, for patients presenting with acute occlusion, surgical resection of the anterior scalene and first rib with venolysis is preferred to thrombectomy, balloon venoplasty, and stenting.

For patients with chronic obstruction, Molina and colleagues report successful approaches based on length of the obstructed segment. For patients with short segment chronic obstruction, they have been successful with saphenous vein patch to the subclavian vein. In patients with a long segment of chronic obstruction, they have treated with either long vein patch with upper thigh saphenous vein or implantation of thoracic aortic homografts with subsequent balloon dilation and implantation of a stent for reobstruction. Venous bypass has also been successfully used in patients with residual stenosis after thoracic outlet decompression.

The need for and duration of anticoagulation for patients treated with catheter-directed thrombolysis followed by decompression is unclear. Some authors maintain that no anticoagulation is needed when good surgical outcomes are obtained, while others have anticoagulated for two to three months. All patients who present with primary venous thrombosis should undergo a workup for a hypercoagulable state, the most common of which are mutations in coagulation factor V, protein C and S deficiencies, and antithrombin III. Because of a 40%-60% rate of recurrent thrombosis, these patients are maintained indefinitely on warfarin.

Prognosis

The prognosis after axillary-subclavian vein thrombosis is dependent on the cause of the condition. Most patients experience fairly rapid resolution of their initial presenting symptoms. For patients with secondary forms of this disease, the outcome is dependent on resolution of the underlying condition, such as a malignancy. For patients with Paget–Schroetter syndrome who undergo thoracic outlet decompression, excellent outcomes, characterized by continued venous patency and absence of symptoms of CVI, are typical. In contrast, chronic axillary-subclavian vein thrombosis with symptoms persisting for over 3 months does not often respond to thrombolysis, mechanical thrombolysis, or prolonged anticoagulation and may cause significant long-term disability.

PULMONARY THROMBOEMBOLISM

General Considerations

Pulmonary thromboembolism is responsible for up to 50,000 deaths each year in the United States. It is the third-leading cause of death among hospitalized patients, yet only 30%-40% of those with pulmonary thromboembolism have suspected DVT at the time of diagnosis. Efforts directed at reduction in the mortality rate of pulmonary thromboembolism demand an aggressive approach to the prevention of DVT and diagnosis of pulmonary thromboembolism in patients identified to be at high risk.

Pulmonary thromboemboli arise from a number of sources. Air embolism can occur during the placement or removal of central venous catheters intraoperatively during operation on large venous vessels. Amniotic fluid emboli may occur during active labor. Fat emboli from long bone fractures cause a syndrome characterized by respiratory insufficiency, coagulopathy, encephalopathy, and an upper body petechial rash. Other less common causes of pulmonary emboli include septic emboli, tumor emboli from atrial myxoma or IVC extension of renal cell carcinoma, and parasitic emboli. However, DVT remains the most common source of pulmonary thromboemboli. Up to 60% of patients with untreated proximal lower extremity DVT may develop pulmonary thromboembolism.

Fewer than 10% of pulmonary thromboemboli will produce pulmonary infarction. The pathophysiology of PE depends on the size and frequency of the emboli as well as the condition of the underlying lung. Obstruction of large pulmonary arteries results in increases in pulmonary artery pressure and acute right-ventricular failure, but many of the clinical manifestations of pulmonary thromboembolism result from release of vasoactive amines that cause severe pulmonary vasoconstriction. Vasoconstriction leads to increased physiologic dead space and systemic hypoxia from a right-to-left shunt. Reflex bronchial vasoconstriction is also common.

Clinical Findings

A. Symptoms and Signs

Signs and symptoms associated with PE are notoriously vague. Dyspnea and chest pain are present in up to 75% of patients with pulmonary thromboembolism. However, these symptoms are nonspecific, especially in patients who may have underlying cardiopulmonary disease. Tachycardia, tachypnea, and altered mental status are highly suggestive findings in an at-risk population. The classic triad of dyspnea, chest pain, and hemoptysis is present in only 15% of patients with pulmonary thromboembolism. Pleural friction rub and the S1Q3T3 morphology on electrocardiography are even less common findings.

B. Imaging and Other Diagnostic Studies

Chest x-ray is most often normal but may show a pleural cap. Electrocardiography may reveal new-onset atrial fibrillation, evidence of right-heart strain, or ischemic changes, but in most cases only acute sinus tachycardia and nonspecific ST and T wave changes are identified. Arterial blood gas determination reveals hypoxia and often a respiratory alkalosis or increased arterial-alveolar oxygen gradient. Plasma D-dimer levels are elevated in the presence of both pulmonary thromboembolism and acute DVT, but this test lacks sufficient specificity to be of primary diagnostic value. In acute massive or submassive PE resulting in hemodynamic instability (systolic blood pressure < 90 mm Hg) and right heart strain leading to myocardial ischemia, cardiac troponins may be elevated. Plasma B-type natriuretic peptide may also be elevated in right heart strain, though it is similarly not specific enough to be used alone for diagnosis of PE.

CT angiography is now the preferred imaging modality used for the diagnosis of PE, due to its wide availability, sensitivity and specificity, characterization of vascular and nonvascular structures, and exceptional speed (Figure 35–5). CT angiograms (CTA) are more accurate than the previously commonly used ventilation-perfusion scan, and when compared to pulmonary angiography, CTAs are less invasive, less time consuming, and less expensive. For CTA, the patient presentation must match the results of the CTA, for the most accurate determination of the diagnosis of PE. For patients in whom massive PE is suspected but contrast agent administration is undesirable, a bedside echocardiogram may be performed to evaluate for right heart dysfunction as an indication of hemodynamically significant PE. Intravascular ultrasound (IVUS) has also been used for bedside evaluation.

Treatment

A. Anticoagulation

Rapid anticoagulation remains the mainstay of treatment of PE. Heparin, the pentasaccharide fondaparinux, or LMWH anticoagulation is started as soon as the diagnosis is made after initial stabilization with ventilatory support and vasopressor medications. While these drugs are not thrombolytic, they allow the body’s fibrinolytic system to function unopposed. Thrombolysis is considered for large clot burden, severe respiratory compromise, hemodynamic instability, or right-heart failure. When compared with heparin alone, thrombolytic therapy speeds the resolution of pulmonary emboli in the first 24 hours. The disadvantages of lytic therapy include its greater cost and higher risk of significant bleeding complications.

B. Inferior Vena Cava Interruption

IVC interruption is considered in patients who have extension of venous thrombus on adequate anticoagulant therapy, patients in whom heparin anticoagulation is contraindicated, patients who have had a complication of anticoagulation, or patients who have had recurrent DVT or PE despite therapeutic anticoagulation. More recently, temporary or permanent IVC filters have been placed prophylactically in high-risk patients such as those with unresectable cancer or major trauma. Interestingly, as insertion of an IVC filter does not completely eliminate the risk of a PE, may increases the risk of DVT, and does nothing to prevent postthrombotic syndrome (PTS), the current guidelines suggest that patients who have an IVC filter should receive the standard course of anticoagulation if the contraindication to anticoagulation is no longer applicable.

Historically, IVC interruption was performed as an open surgical procedure, involving ligation or plication of the infrarenal vena cava or placement of a serrated clip to “strain” blood returning to the right atrium. The Greenfield filter, developed in 1973, was initially deployed by venous cutdown. Multiple devices are now available for fluoroscopically guided percutaneous placement through a range of sheath sizes from 6F to 12F and are introduced into the common femoral vein or, in cases of femoral thrombus, into the internal jugular vein. Diagnostic inferior venacavogram is essential prior to placing the filter to exclude the presence of a duplicated IVC because lower extremity DVT might still serve as a source of emboli. The presence of thrombus within the IVC, the diameter of the IVC, and identification of the level of the renal veins are also important to evaluate.

The development and increased use of retrievable IVC filters for both prophylaxis and therapy of VTE is largely driven by the results of the PREPIC study. This study remains the only prospective, randomized clinical trial comparing IVC filters to anticoagulation alone. At 8 years, the study suggested a higher incidence of recurrent DVT in patients who were randomized to the IVC filter arm of the study compared to group who received anticoagulation only. This study suggested that patients with IVC filters in placed had a significantly higher risk of recurrent DVT than patients treated with anticoagulation alone. There was no difference in the incidence of PTS between study groups but patients with IVC filters in place had significantly lower rates of PE over the course of the study compared to the anticoagulation group. While there is a multitude of devices available and many small observational studies that suggest that retrievable filters are safe and effective, no other prospective comparison studies have yet to be performed.

Additionally, alternative imaging modalities (other than venography) are successfully being used to place filters. Specifically, devices are being successfully and safely deployed under ultrasound guidance, both intravascular and transabdominal ultrasound. Kassavin and colleagues recently described the transition from combined use of IVUS-guided and traditional techniques (such as venography) for IVC filter placement to the use of IVUS as the primary road mapping tool had a learning curve of only approximately 20 cases. Compared to traditional placement, the use of IVUS for IVC filter deployment lacks the risks of prolonged radiation exposure and nephrotoxic contrast agents while diminishing the case duration and overall cost.

C. Surgical Treatment

Hemodynamically unstable patients in whom thrombolytic therapy has failed or cannot be instituted require percutaneous or open surgical extraction of the thrombus. Open surgical pulmonary embolectomy is reserved for patients who develop intractable hypotension, those who fail trans-catheter pulmonary embolectomy, and those who have tumor or foreign body emboli. Catheter techniques involve mechanical thrombolysis or removal of intact pulmonary emboli using a suction embolectomy device.

Prognosis

PE is one of the most frequent causes of preventable hospital death. Prevention by use of DVT prophylaxis and early diagnosis by selective testing of high-risk patients are essential steps to reducing the morbidity of this disease. The placement of IVC filters in selected patients can aid in prevention of pulmonary embolus but does nothing to treat the underlying disease process (venous thromboembolic disease) or prevent the long-term sequelae of DVT-PTS.

SUPERFICIAL THROMBOPHLEBITIS

General Considerations

Superficial thrombophlebitis (SVT) may appear spontaneously in patients with varicose veins, in pregnant or postpartum women, or in patients with thromboangiitis obliterans or Behçet disease. It may also occur after intravenous therapy or in an area of localized trauma. The presence of superficial phlebitis, particularly if it occurs in a migratory manner, suggests the presence of an abdominal cancer such as carcinoma of the pancreas (Trousseau thrombophlebitis). The most common vein affected is the greater saphenous vein and its branches. In up to 40% of cases, a simultaneous DVT exists, and duplex imaging is a must in these situations. Pulmonary emboli are rare unless extension into the deep venous system occurs.

Clinical Findings

The patient usually presents complaining of localized extremity pain and redness. Areas of induration, erythema, and tenderness correspond to dilated and often thrombosed superficial veins. Over time, a firm cord may develop. Generalized edema is absent unless the deep veins are involved. The presence of fever and shaking chills suggests septic or suppurative phlebitis, which occurs most commonly as a complication of intravenous cannulation.

Differential Diagnosis

Superficial thrombophlebitis must be distinguished from ascending lymphangitis, cellulitis, erythema nodosum, erythema induratum, and panniculitis. Unlike these other disorders, superficial phlebitis tends to be well localized over a superficial vein.

Treatment

The primary treatment of superficial venous thrombophlebitis is the administration of nonsteroidal anti-inflammatory drugs, local heat, elevation, and support stockings or elastic wraps. Ambulation is encouraged. In most cases, symptoms will resolve within 7-10 days. Excision of the involved vein is recommended for symptoms that persist over 2 weeks despite treatment or for recurrent phlebitis in the same vein segment. If there is progressive proximal extension with involvement of the saphenofemoral junction or cephalic-subclavian junction, ligation and resection of the vein at the junction should be performed. More recently, cases in which endovenous thermal ablation was used in the treatment of superficial thrombophlebitis has been reported but not usually during the acute phase of the disease process. Alternatively, LMWH has been studied in the treatment of superficial thrombophlebitis given its anti-­inflammatory and antithrombotic effects. In a randomized trial by Rathbun and colleagues comparing daily dalteparin versus ibuprofen three times daily for up to 14 days, dalteparin was found to be superior in preventing extension of superficial thrombophlebitis at 14 days with similar relief of pain.

The approach to treating SVT is variable, as there is no general consensus on ideal treatment. Reports of less than 10% to approximately 40% of presentation of SVT also presents with associated acute DVT. The occurrence of concomitant PE has been reported from 0.5% to 4% in symptomatic patients. Approximately 60%-80% of SVT cases involve the great saphenous vein and 10%-20% of cases involve the small saphenous veins, with involvement of the upper extremity veins occurring next in frequency. The association between SVT and both DVTs and PEs increases as the phlebitis extends toward the saphenofemoral junction. The treatment approach therefore depends on the location, presence of concomitant DVT, and the presence of additional risk factors such as hypercoagulable disorders. Involvement of the junction warrants aggressive treatment with LMWH to prevent further extension into the deep venous system. A recent Cochrane review involving 26 studies and 5521 participants assessed the current approach to patients with superficial thrombophlebitis of the legs. Fondaparinux at a prophylactic dose given for 45 days was associated with lower rates of recurrence and extension of superficial thrombophlebitis compared to placebo. Both NSAIDS and LMWH reduced extension or recurrence when compared to placebo. When comparing LMWH with surgical intervention (saphenofemoral disconnection), both were comparable in reduction of VTE events, though surgery was associated with a statistically insignificant lower risk of extension or recurrence. Alternatively, venous stripping plus elastic stockings demonstrated a lower, nonsignificant incidence of VTE compared with elastic stockings alone. In general, surgical treatment with ligation of the great saphenous vein at the saphenofemoral junction allows for superior symptomatic relief of pain, while medical management with anticoagulants appears superior for minimizing complications and preventing subsequent DVT/PE.

Septic thrombophlebitis requires treatment with broad-spectrum intravenous antibiotics. If rapid resolution of the cellulitis occurs, no treatment beyond a short course of antibiotics is required. However, if the patient becomes ­septic, excision of the entire infected vein is required. Catheter removal is required in cases involving central venous catheter infection. In patients refractory to standard medical therapy yet poor candidates for invasive surgical therapy, endovascular treatment using thrombectomy devices, balloon angioplasty, and local intraluminal infusion of antibiotics has been reported. Thrombolytic therapy and mechanical thrombectomy remain options for the treatment of the thrombosed vein segment.

Prognosis

Most episodes of uncomplicated superficial thrombophlebitis respond to conservative management. Cases in which extension into the deep venous system occurs can be associated with thromboembolism.

CHRONIC VENOUS INSUFFICIENCY

CVI can result from congenital venous valvular insufficiency or can result from previous venous thrombosis. In the former circumstance, it is called CVI while in the latter circumstance, it is called the PTS. Varicose veins (also a manifestation of venous insufficiency), CVI, and PTS occur in 76/100,000 person-years, and it has been estimated that 6-7 million Americans suffer from stasis pigmentation changes in the legs with another 400,000-500,000 patients with skin ulceration. Treatment costs are in the billion dollar range. The basic physiologic abnormality in patients with CVI is chronic elevation of venous pressure. The normal venous capacitance can accommodate large-volume changes that occur during exercise with only minimal changes in venous pressure. However, with calf muscle pump dysfunction and valvular reflux, blood pools in the lower extremities and venous hypertension occurs, leading to venous hypertension. Outflow obstruction from proximal obstruction can also produce venous hypertension, resulting in “venous claudication” as the deep venous system fills with blood during exercise. The leg becomes painful, swollen, and heavy (especially with exercise), mimicking arterial insufficiency. Severity of chronic venous disease has been associated with older age and higher body mass index.

Valvular incompetence of the deep veins can be congenital or result from damage following phlebitis, varicose veins, or DVT. The best estimate for the incidence of CVI is approximately 30% after 8-year follow-up. Chronic venous stasis changes are centered in the “gaiter areas” around the ankles. This is the location of the commonly affected perforator veins and is a region with sparse soft tissue support to withstand elevated venous pressures. Brawny edema is produced by extravasation of plasma fluid, red blood cells, and plasma proteins. Lysis of red blood cells results in deposition of hemosiderin, which creates a brownish discoloration. Leukocytes become sequestered in the microcirculation, leading to capillary occlusion and release of superoxide radicals, proteolytic enzymes, and growth factors. Macrophages and T lymphocytes are primary mediators of this inflammatory response, which results in fibroblast activation and scarring and fibrosis of the subcutaneous tissues. Ultimately, this fibrosis results in compromised skin perfusion and ulceration.

Clinical Findings

A. Symptoms and Signs

Both isolated saphenous vein incompetence and deep venous insufficiency can lead to venous varicosities and chronic venous stasis changes. One of the first symptoms to develop is usually ankle and calf edema. Involvement of the foot and toes suggests lymphedema. Typically, the edema is worse at the end of the day and improves with leg elevation. Additional symptoms may include aching, tingling, burning, muscle cramps, heaviness, sensations of throbbing, and leg fatigue. Longstanding disease is characterized by stasis dermatitis, hyperpigmentation, brawny induration, and ulceration. Venous stasis ulcers are large, painful, and irregular in outline. They have a shallow, moist granulation bed, occur in the gaiter area on the medial or lateral aspects of the ankle, and are often accompanied by stasis dermatitis and stasis pigmentation changes.

B. Imaging and Other Diagnostic Studies

Duplex ultrasound can identify the presence and location of incompetent superficial and deep veins and perforating veins and has been used to evaluate the function of individual venous valves. Current guidelines recommend selective scanning of perforating veins in patients with CVI, Duplex imaging has become the most important test of venous pathophysiology today and should be performed in every patient with CVI and PTS. However, it does not easily assess calf muscle pump function or the presence of proximal obstruction. These concerns are addressed with use of other tests, such as air plethysmography, which gives a quantitative assessment of venous reflux (by the venous filling index), calf muscle pump function (by the ejection fraction), and overall venous function (by residual volume function). These measurements help to stratify patients into treatment groups.

Determination of functional outflow obstruction requires venography with or without pressure measurement, although intravascular ultrasound (IVUS) is also very useful to determine the presence or absence of venous obstruction. Descending phlebography involves injection of contrast media into the common femoral vein to test the valves during normal breathing and with a forced Valsalva maneuver. Using this technique, pathologic reflux can be identified in patients with postthrombotic damage. Such testing is reserved in anticipation of surgical correction of the venous pathology if duplex scanning does not provide definite information on pathophysiology.

Differential Diagnosis

Congestive heart failure and chronic liver and kidney disease must be considered in the differential diagnosis of bilateral lower extremity edema. Lymphedema is characterized by nonpitting edema of the dorsum of the foot and toes as well as the calf and generally is not associated with skin pigment changes, dermatitis, or ulceration. Severe arterial insufficiency produces ulcers that are painful, well circumscribed, and located over pressure points on the distal end of the extremity and foot. Ulcers due to autoimmune diseases, erythema nodosum, and fungal infections are distinguished by appearance and distribution.

Treatment

Venous insufficiency is an incurable but manageable problem. Most patients respond well to a conservative treatment program composed of intermittent leg elevation, regular exercise to improve calf muscle pump function, and the use of surgical elastic graduated compression stockings. Although the mechanism by which elastic compression improves the symptoms of CVI has not been clearly established, recent work suggests that external compression may restore competency of dilated valve cusps and affect venoarterial reflex. Most venous ulceration will improve with leg elevation, external compression, and local wound care. Compression can be achieved with an inelastic bandage such as an Unna boot, an occlusive wound dressing covered by elastic bandage wrapping, or surgical support stockings.

Surgery is indicated for a small percentage of patients with nonhealing ulcers or disabling symptoms refractory to conservative management. The three main categories of procedures include those ablative procedures on the superficial venous system in the face of superficial venous reflux, antireflux procedures, and bypass operations for obstruction. If superficial venous reflux is a significant component of the total venous reflux present, then superficial ablation is appropriate. Such ablation has been found successful in preventing recurrent venous ulceration and has also been found to improve patients’ symptoms of both varicose veins and venous reflux. Ablation may be performed with traditional open surgical ligation and stripping or the more recent endovenous procedures such as radiofrequency ablation or endovenous laser therapy. The pathology must be accurately characterized so that an appropriate operative strategy can be developed. The most common abnormality in patients with CVI is incompetence of the popliteal or tibial veins; 50%-60% of patients have incompetent perforators.

Perforating vein interventions are typically performed in patients with recurrent venous ulcers or demonstrated incompetence of perforating veins under the area of ulceration. Since its introduction in the 1980s to the late 2000s, subfascial endoscopic perforator vein surgery (SEPS) was the technique of choice for perforator ablation, as studies revealed that it resulted in a significant lower rate of wound infections and recurrent ulcers compared to the open Linton procedure. However, continued advancements in perforator ablation techniques in more recent years has led to increased use of percutaneous ablation of perforators (PAPS), radiofrequency ablation (RFA), endovenous laser ablation, and sclerotherapy in addition to SEPS. Current guidelines recommend against selective treatment of incompetent perforating veins in patients with simple varicose veins. However, in perforating veins which meet “pathologic” criteria (outward flow ≥500 ms duration, diameter ≥3.5 mm, located beneath healed or open venous ulcer), SEPS, ultrasound-guided sclerotherapy, or thermal ablations are suggested.

While minimally invasive techniques addressing superficial and perforator reflux have advanced, such treatment of deep reflux disease remains challenging. There are both nonthrombotic and postthrombotic etiologies, either of which contributes to the obstructive component of deep reflux disease. Previous surgical options included venous bypass and reconstruction procedures, patch venoplasty, and, specifically in the case of patients for whom iliac-femoral stenosis is confirmed through venography and intravenous ultrasonography (IVUS), venous stenting has been a successful endovascular treatment option. Alhalbouni and colleagues reported the majority of their patients experienced healing of their chronic venous stasis ulcers after stenting of stenotic lesions found by IVUS. Raju et al. describe 5-year continued freedom from venous ulcer after iliac stenting to near 90%, underscoring both the role of obstruction in the pathophysiology and the effectiveness of relieving such obstruction.

LYMPHEDEMA

General Considerations

Much less is known about the fluid dynamics of the lymphatic system than of the venous or arterial system. Most energy for lymph propulsion arises from the intrinsic lymphatic smooth muscle contractions that occur rhythmically. Lymphatic luminal pressures are usually 30-50 mm Hg and can exceed arterial pressure under special circumstances. The lymphatic system carries interstitial fluid and macromolecular proteins lost from the capillaries, as well as infectious agents and foreign material, back into the central circulation. Two to four liters a day of lymph drain into the subclavian vein.

The fundamental mechanism responsible for lymphedema formation is impaired lymph flow out of the extremity. Primary lymphedema includes idiopathic types of lymphedema without an identifiable etiology, and the more commonly recognized type due to abnormal lymphatic development, most often hypoplasia resulting in severe reduction in the number of lymphatics and the lymphatic diameters. It is classified by age at onset of the disease. Congenital lymphedema develops before 1 year of age, is usually bilateral, and affects men more than women; if familial, it is known as Milroy disease. More often, lymphedema develops during adolescence (lymphedema praecox) and is unilateral; there is a 10:1 female predominance. Lymphedema occurring after age 35 is referred to as lymphedema tarda.

Secondary lymphedema results from a wide variety of disease processes that cause obstruction to the lymphatic system. The most common of these is surgical excision and radiation to the axillary or inguinal lymph nodes as part of the treatment of breast cancer, cervical cancer, prostate cancer, melanoma, and soft tissue tumors. Many of these neoplasms tend to develop regional lymphatic metastases before progressing to distant metastatic disease, and their treatment commonly involves complete lymph node dissection of the involved territory. Of note, secondary lymphedema may arise at any time postoperatively, including years and decades after the operation. Less common causes of secondary lymphedema are bacterial and fungal infections, trauma, and lymphoproliferative diseases. In many developing countries, lymphatic obstruction due to filariasis is caused by three different parasites: Wuchereria bancrofti, Brugia malayi, and Brugia timori.

Clinical Manifestations

A. Symptoms, Signs, and Assessment

The history of the disease process will usually define the cause of the lymphedema. Development of painless edema in an adolescent girl with a family history of lymphedema would indicate primary lymphedema as a diagnosis. A history of lymph node dissection, irradiation, or the presence of a parasitic infection suggests secondary lymphedema.

Lymphedema development is usually slowly progressive and painless. In the early stages, the edema is pitting, but as the disease progresses, chronic fibrosis occurs and the edema becomes nonpitting. The distribution of edema is also characteristic. It is usually centered on the ankle (Figure 35–6) and is most pronounced on the dorsum of the foot, producing a buffalo hump appearance. Unlike edema of venous stasis disease, lymphedema also often involves the toes. In the early stages, the skin is normal, but skin thickening and hyperkeratosis occurs with longstanding disease. A chronic eczematous dermatitis may ensue.

Objective assessment is most commonly performed by measuring the circumference of the extremities, with the difference threshold of greater than 2 cm to define lymphedema. Additionally, water displacement is used to assess limb volume. The difference between the two arms before and after surgery of over 200 mL has been used to identify secondary lymphedema.

Rarely, lymphangiosarcoma or angiosarcoma may develop as a complication of chronic lymphedema. This neoplastic transformation of blood vessels and lymphatics is called Stewart–Treves syndrome.

B. Imaging Studies

Venous duplex scans are performed to rule out venous insufficiency and exclude venous obstruction. CT and MRI are useful tests in patients with suspected secondary lymphedema from unknown malignancy. Lymphangiography has largely been replaced by radionuclide lymphoscintigraphy, the gold standard for evaluation of lymphatic function. A subcutaneous injection of 99mTc-labeled substance is injected into the first and second web-space of the toes or fingers, and its movement, transition time, and activity are interpreted. Lymphoscintigraphy carries minimal risk, and its use in conjunction with duplex scans permits the detection of lymphatic dysfunction and lymph nodes and provides information on lymph transport and reflux.

Differential Diagnosis

A variety of diseases can result in bilateral lower extremity edema. These include congestive heart failure, pulmonary hypertension, chronic renal or hepatic insufficiency, and hypoproteinemia. In patients with unilateral leg edema, differential diagnosis includes congenital vascular malformations, chronic venous insufficiency, and reflex sympathetic dystrophy.

Treatment

Lymphedema is a chronic disease for which there is no complete cure. However, a variety of conservative measures can substantially reduce the risk of further complications and disability.

No drug therapy is effective. Use of benzopyrones (to increase lymphatic transport by macrophages) has shown some benefit. Diuretics can be useful for acute exacerbation of edema secondary to infection or for coexisting venous stasis disease, but these agents are not recommended for long-term use in lymphedema.

The mainstay of treatment is external compression and meticulous skin care. Mechanical reduction of lymphedema can best be achieved with a program of frequent leg elevation, manual lymphatic drainage massage, low-stretch wrapping techniques, and intermittent pneumatic compression (IPC). Decongestive lymphatic therapy (DLT) is traditionally the first line of treatment regardless of primary or secondary etiology. DLT is composed of manual lymphatic drainage, compression therapy with bandages and IPC, and movement exercises. Many different devices are available for use on the leg, and sleeves can be custom fit for patients with postmastectomy arm lymphedema. Graduated compression stockings maintain the limb after reduction by pneumatic compression. Good skin care is imperative in order to prevent infection. Moisturizing lotions should be applied regularly, especially after showering or bathing. Drying and cracking of the skin can create portals of entry for bacteria. Infection is difficult to eradicate because of disordered lymphatic drainage and can be limb threatening.

The psychologic impact of chronic lymphedema cannot be underestimated. However, with appropriate patient education that results in the prevention of chronic infection or massive edema, this problem can be manageable.

Operation may be considered in rare cases of severe functional impairment and recurrent lymphangitis. The approaches are either reductive in nature to minimize bulk, or they are reconstructive to rebuild lymphatic channels. Indications for reductive therapies include massive, incapacitating extremities, and the failure of conservative therapy. The Charles procedure involves excision of all skin and subcutaneous tissue from the tibial tuberosity to the lateral head of the fibula and wound coverage by a split thickness skin graft. Due to unpredictable cosmetic outcomes and associated complications such as cellulitis and sepsis, many variations of this procedure now exist with reported decrease in morbidity. More recently, liposuction-circumferential suction-assisted lipectomy has been successful in treating upper-extremity lymphedema secondary to breast cancer therapy. In this scenario, fat is the primary cause of swelling and not fluid, thus lymph reconstruction and conservative measurements are ineffective.

The application of reconstructive techniques is most successful in early disease, when the lymphatics are relatively healthy. Lymphatic channels are rebuilt via microsurgical methods of lympho-venous or lympho-venous-lymphtic bypass anastomosis, lympho-lymphatic segmental interposition, or free lymph node transplantation. Campisi and colleagues present the largest series to date evaluating lymphatic reconstruction, with 1800 patients with primary and secondary lymphedema treated over 30 years with lymphatic-venous anastomoses. Their study demonstrates 87% of their subjects reported subjective improvement and 83% showed significant volume reduction. Notably, more than 90% of these patients were in Campisi stage II and III lymphedema with persistent edema, but still at a relatively early stage before the onset of fibrosis or severe limb deformation. As the disease progresses and irreversible damage inevitably results, there is little success in restoring flow or reducing fibrosclerotic tissue.

LYMPHANGITIS

General Considerations

Lymphangitis is usually caused by a hemolytic streptococcal or staphylococcal infection that arises in an area of cellulitis near an open wound. Multiple long red streaks can be seen coursing toward the regional lymph nodes. Severe systemic manifestations include tachycardia, fever, chills, and malaise, which untreated can lead to sepsis and death.

Clinical Findings

A. Symptoms and Signs

Pain at the site of the initial wound is present. High fevers develop rapidly. The streaks may be faint in appearance initially, especially in dark-skinned patients. Regional lymph nodes are often enlarged and tender.

B. Laboratory Findings

An elevated white blood cell count associated with a left shift is almost universally present. Blood and wound cultures should be obtained routinely.

Differential Diagnosis

Lymphangitis should be distinguished from superficial thrombophlebitis, which is usually localized to a single venous segment often with a palpable cord. Patients with thrombophlebitis usually do not appear toxic, as do patients with lymphangitis. Cat-scratch fever should always be considered when lymphadenitis is present. It is also important to differentiate cellulitis and severe soft tissue infections from lymphangitis. In general, lymphangitis is characterized by its superficial location and the linear pattern of erythema.

Treatment

The extremity should be elevated and warm compresses applied. Analgesics and intravenous antibiotics should be instituted immediately. Examination of the wound should be made to determine the need for debridement or incision and drainage of an abscess.

Prognosis

Delayed or inadequate therapy can lead to overwhelming sepsis and death. Aggressive institution of appropriate antibiotic therapy and wound care will usually control the infection within 48-72 hours.