Chapter 24: Venous and Lymphatic Disease

1. Thrombolytic therapy, surgical thrombectomy, and placement of inferior vena cava filters are adjunctive treatments that may be indicated in patients with extensive and complicated venous thromboembolism.

2. Deep vein thrombosis (DVT) and pulmonary embolism are frequent complications after major abdominal and orthopedic procedures. The risk is further increased in patients with malignancy and a history of venous thromboembolism. Options for DVT prophylaxis include intermittent pneumatic compression, use of graduated compression stockings, and administration of low-dose unfractionated heparin, low molecular weight heparin, fondaparinux, and vitamin K antagonists. However, prophylaxis should be stratified based on the patient's level of risk.

3. In patients with established DVT, unfractionated heparin, low molecular weight heparin, and fondaparinux are options for initial antithrombotic therapy. The duration and type of long-term anticoagulation should be stratified based on the ­provoked or unprovoked nature of the DVT, the location of the DVT, previous occurrence of DVT, and presence of concomitant malignancy.

4. Saphenous vein stripping, endovenous laser treatment, and radiofrequency ablation are effective therapies for patients with saphenous vein valvular insufficiency. Concomitant varicose veins may be managed with compression therapy, sclerotherapy (for smaller varices), and phlebectomy.

5. The mainstay of treatment for chronic venous insufficiency is compression therapy. Sclerotherapy, perforator vein ligation, and venous reconstruction may be indicated in patients in whom conservative management fails.

6. Lymphedema is categorized as primary (with early or delayed onset) or secondary. The goals of treatment are to minimize edema and prevent infection. Lymphatic massage, sequential pneumatic compression, use of compression garments, and limb elevation are effective forms of therapy.

Veins are part of a dynamic and complex system that returns low-nutrient deoxygenated blood to the heart. Venous blood flow is dependent on multiple factors such as gravity, venous valves, the cardiac and respiratory cycles, blood volume, and the calf muscle pump. Alterations in the intricate balance of these factors can result in venous pathology.

Structure of Veins

Veins are thin-walled, highly distensible, and collapsible. Their structure specifically supports the primary functions of veins to transport blood toward the heart and serve as a reservoir to prevent intravascular volume overload.

The venous intima is composed of a nonthrombogenic endothelium with an underlying basement membrane and an elastic lamina. The endothelium produces endothelium-derived relaxing factors such as nitric oxide and prostacyclin, which help maintain a nonthrombogenic surface through inhibition of platelet aggregation and promotion of platelet disaggregation.¹ Circumferential rings of elastic tissue and smooth muscle located in the media of the vein allow for changes in vein caliber with minimal changes in venous pressure. The adventitia is most prominent in large veins and consists of collagen, elastic fibers, and fibroblasts. When a vein is maximally distended, its diameter may be several times greater than that in the supine position.

In the axial veins, unidirectional blood flow is achieved with multiple venous valves. The inferior vena cava (IVC), common iliac veins, portal venous system, and cranial sinuses are valveless. In the axial veins, valves are more numerous distally in the extremities than proximally. Each valve consists of two thin cusps of a fine connective tissue skeleton covered by endothelium. Venous valves close in response to cephalad-to-caudal blood flow at a velocity of at least 30 cm/s.²

Lower Extremity Veins

Lower extremity veins are divided into superficial, deep, and perforating veins. The superficial venous system lies above the uppermost fascial layer of the leg and thigh and consists of the great saphenous vein (GSV) and small saphenous vein (SSV) and their tributaries. The GSV originates from the dorsal pedal venous arch and courses cephalad, anterior to the medial malleolus, entering the common femoral vein approximately 4 cm inferior and lateral to the pubic tubercle. The saphenous nerve accompanies the GSV medially from the ankle to the level of the knee and supplies cutaneous sensation to the medial leg and ankle. The SSV originates laterally from the dorsal pedal venous arch and courses cephalad in the posterior calf. Most often, it penetrates the popliteal fossa, between the medial and lateral heads of the gastrocnemius muscle, to join the popliteal vein. The termination of the SSV may be quite variable, however, with a proximal extension of the SSV (the vein of Giacomini) frequently connecting with the deep femoral vein or GSV. The sural nerve accompanies the SSV laterally along its course and supplies cutaneous sensation to the lateral malleolar region.

The deep veins follow the course of major arteries in the extremities. In the lower leg, paired veins parallel the course of the anterior tibial, posterior tibial, and peroneal arteries, to join behind the knee forming the popliteal vein. Venous bridges connect the paired veins in the lower leg. The popliteal vein continues through the adductor hiatus to become the femoral vein. In the proximal thigh, the femoral vein joins with the deep femoral vein to form the common femoral vein, becoming the external iliac vein at the inguinal ligament.

Multiple perforator veins traverse the deep fascia to connect the superficial and deep venous systems. Potentially clinically important perforator veins are the Cockett and Boyd perforators. The Cockett perforator veins drain the medial lower leg and are relatively constant. They connect the posterior arch vein (a tributary to the GSV) and the posterior tibial vein. They may become varicose or incompetent in venous insufficiency states. The Boyd perforator veins connect the GSV to the deep veins approximately 10 cm below the knee and 1 to 2 cm medial to the tibia.

Venous sinuses are thin-walled, large veins located within the substance of the soleus and gastrocnemius muscles. These sinuses are valveless and are linked by valved, small venous channels that prevent reflux. A large amount of blood can be stored in the venous sinuses. With each contraction of the calf muscle bed, blood is pumped out through the venous channels into the main conduit veins to return to the heart.

Upper Extremity Veins

As in the lower extremity, there are deep and superficial veins in the upper extremity. Deep veins of the upper extremity are paired and follow the named arteries in the arm. Superficial veins of the upper extremity are the cephalic and basilic veins and their tributaries. The cephalic vein originates at the lateral wrist and courses over the ventral surface of the forearm. In the upper arm, the cephalic vein terminates in the infraclavicular fossa, piercing the clavipectoral fascia to empty into the axillary vein. The basilic vein runs medially along the forearm and penetrates the deep fascia as it courses past the elbow in the upper arm. It then joins with the deep brachial veins to become the axillary vein. The median cubital vein joins the cephalic and the basilic veins on the ventral surface of the elbow.

The axillary vein becomes the subclavian vein at the lateral border of the first rib. At the medial border of the scalenus anterior muscle, the subclavian vein joins with the internal jugular vein to become the brachiocephalic vein, with the subclavian vein coursing anterior to the scalenus anterior muscle. The left and right brachiocephalic veins join to become the superior vena cava, which empties into the right atrium.

Clinical Evaluation

Evaluation of the venous system begins with a detailed history and physical examination. Risk factors for acute and chronic venous disease are identified. They include increased age, history of venous thromboembolism (VTE), malignancy, trauma and spinal cord injury, hospitalization and immobilization, obesity, nephrotic syndrome, pregnancy and the recently postpartum state, oral contraceptive use or hormone replacement therapy, varicose veins, and hypercoagulable states, as well as the postoperative state. Venous pathology is often, but not always, associated with visible or palpable signs that can be identified during the physical examination. There is variation among individuals in the prominence of superficial veins when the person is standing (Fig. 24-1). The superficial veins of a lean athletic person, even when normal, will appear large and easily visualized, but these veins will be far less obvious in the obese individual. Possible signs of superficial venous abnormalities are listed in Table 24-1. The deep veins cannot be directly assessed clinically, and abnormalities within them can only be inferred indirectly from changes found on clinical examination.

Chronic venous insufficiency (CVI) may lead to characteristic changes in the skin and subcutaneous tissues in the affected limb. CVI results from incompetence of venous valves, venous obstruction, or both. Most CVI involves venous reflux, and severe CVI often reflects a combination of reflux and venous obstruction. It is important to remember that although CVI originates with abnormalities of the veins, the target organ of CVI is the skin, and the underlying physiologic and biochemical mechanisms leading to the cutaneous abnormalities associated with CVI are poorly understood. A typical leg affected by CVI will be edematous, with edema increasing over the course of the day. The leg may also be indurated and pigmented with eczema and dermatitis. These changes are associated with excessive proteinaceous capillary exudate and deposition of a pericapillary fibrin cuff that may limit nutritional exchange. In addition, an increase in white blood cell trapping within the skin microcirculation in CVI patients may lead to microvascular congestion and thrombosis. Subsequently, white blood cells may migrate into the interstitium and release necrotizing lysosomal enzymes, potentially leading to tissue destruction and eventual ulceration.

Fibrosis can eventually develop from impaired nutrition, chronic inflammation, and fat necrosis (lipodermatosclerosis). Hemosiderin deposition due to the extravasation of red cells and subsequent lysis in the skin contributes to the characteristic pigmentation of chronic venous disease (Fig. 24-2). Ulceration can develop with longstanding venous hypertension and is associated with alterations in microcirculatory and cutaneous lymphatic anatomy and function. The most common location of venous ulceration is approximately 3 cm proximal to the medial malleolus (Fig. 24-3).

Trendelenburg’s test is a clinical test, historically important but now rarely used, that can help determine whether incompetent valves are present and in which of the three venous systems (superficial, deep, or perforator) the valves are abnormal. There are two components to this test. First, with the patient supine, the leg is elevated 45° to empty the veins, and the GSV is occluded with the examiner’s hand or with a rubber tourniquet. With the GSV still occluded, the patient stands and the superficial veins are observed for blood filling. The compression on the GSV is released and the superficial veins are observed for filling with blood. A negative result, indicating no clinically relevant venous reflux, is the gradual filling of the veins from arterial inflow. A positive result is the sudden filling of veins with standing while the GSV remains occluded indicating incompetent perforator and deep veins. The GSV valves are incompetent if the second component of the test yields a positive result. Interpretation of the findings of Trendelenburg’s test is subjective, and therefore, it has largely been supplanted by the more objective noninvasive vascular laboratory tests to localize sites of venous reflux.

Noninvasive Evaluation

Before the development of vascular ultrasound, noninvasive techniques to evaluate the venous system were based on plethysmographic techniques. Although a variety of plethysmographic techniques are used in the evaluation of both acute and chronic venous disease, they are all based on the detection of volume changes in the limb in response to blood flow.

Duplex ultrasonography (DUS) augmented by color flow imaging is now the most important noninvasive diagnostic method in the evaluation of the venous system. DUS has become standard for the detection of infrainguinal deep vein thrombosis (DVT), with near 100% sensitivity and specificity in symptomatic patients.³ It is also the preferred method of evaluation for upper extremity venous thrombosis and is useful in the evaluation of CVI by documenting the presence of valvular reflux and venous obstruction. Overlying bowel gas and large body habitus make DUS less applicable to evaluation of intra-abdominal veins. Magnetic resonance venography (MRV) and computed tomography (CT) venography are noninvasive techniques for evaluation of pelvic and intra-abdominal veins.

Invasive Evaluation

Improved accuracy of noninvasive techniques for diagnostic purposes has made the use of invasive procedures more selective. Both venography and intravascular ultrasound (IVUS) are used as adjuncts to percutaneous or open surgical treatment of venous disorders. When planning endovascular or open surgical treatment, venography may be used to identify areas of obstruction in infrainguinal, intra-abdominal, and upper extremity veins as well as reflux in intra-abdominal and infrainguinal veins. IVUS, with access generally via the common femoral vein, is used primarily to assess for occlusive lesions of the iliac veins and appears more sensitive than venography in detecting iliac vein obstruction.

Complications of venography include pain, thrombosis, or hematoma at the puncture site. Pain is lower with nonionic low-osmolality contrast media than with conventional contrast agents (with 18% vs. 44% of patients experiencing discomfort, respectively).⁴ Systemic effects of iodinated contrast media include allergic reaction and risk of renal failure. Postvenography venous thrombosis occurs distal to the venous puncture site in 1% to 9% of patients undergoing venography secondary to intimal damage from the intravenous (IV) contrast agent.⁴ Complications of IVUS are primarily related to the access site.

Epidemiology

Despite increased awareness and use of prophylactic modalities, DVT and pulmonary embolism (PE), or VTE, remain important preventable sources of morbidity and mortality, especially in the surgical patient. The incidence of VTE is approximately 100 per 100,000 people per year in the general population, with 20% of the diagnoses made within 3 months of a surgical procedure. Of the symptomatic patients, one third will present with PE and two thirds with DVT.^5,6 The estimated number of cases of VTE may well be over 600,000 per year in the United States, making it a major U.S. health problem.⁷ Furthermore, death occurs in 6% of DVT and 12% of PE cases within 1 month of diagnosis.⁵ Not only does VTE pose a veritable threat to life, but it also places patients at higher risk for recurrence and post-VTE sequelae such as pulmonary hypertension and postthrombotic syndrome, with 4% and up to 30% incidence, respectively.^8,9,10

Risk Factors

Three conditions, first described by Rudolf Virchow in 1862, contribute to VTE formation: stasis of blood flow, endothelial damage, and hypercoagulability. Of these risk factors, relative hypercoagulability appears most important in most cases of spontaneous VTE, or so-called idiopathic VTE, whereas stasis and endothelial damage likely play a greater role in secondary VTE, or so-called provoked VTE, occurring in association with transient risk factors such as immobilization, surgical procedures, and trauma. Identifiable risk factors for VTE generally relate to one of the conditions described by Virchow. Often more than one risk factor is present. Specific risk factors for VTE are listed in Table 24-2.

The more common acquired VTE risk factors include older age (>40 years), hospitalization and immobilization, hormone replacement and oral contraceptive therapy, pregnancy and the recently postpartum state, prior VTE, malignancy, major surgery, obesity, nephrotic syndrome, trauma and spinal cord injury, long-haul travel (>6 hours), varicose veins, antiphospholipid syndrome, myeloproliferative disorders, and polycythemia. Heritable risk factors include male sex, factor V Leiden mutation; prothrombin 20210A gene variant; antithrombin, protein C, and protein S deficiencies; and dysfibrinogenemias. In some patients, the cause of the thrombophilia may have both a heritable and an acquired component. These mixed causes include homocysteinemia; factor VII, VIII, IX, and XI elevation; hyperfibrinogenemia; and activated protein C resistance in the absence of factor V Leiden.¹¹ There may be a synergistic effect when particular multiple inherited and acquired risk factors are present in the same patient.

Other patient-specific factors associated with venous thrombosis include the traditional cardiovascular risk factors of obesity, hypertension, and diabetes. VTE is more common in whites and African Americans than Asians and Native Americans.^12,13 Certain gene variants (single nucleotide polymorphisms) are also associated with a mildly increased risk for VTE, and their presence may interact with other risk factors to increase the overall risk for venous thrombosis.¹⁴

Anatomic factors may also contribute to development of DVT. At the site where the right iliac artery crosses over the left iliac vein, the left iliac vein may become chronically narrowed predisposing to iliofemoral venous thrombosis, so-called May-Thurner syndrome. External compression of major veins by masses of various types can also lead to venous thrombosis.

Many cases of VTE are potentially preventable. Accordingly, in current clinical practice, preoperative VTE risk assessment is becoming increasingly common to identify patients at moderate and high risk. Scoring systems have been developed that take into account the number of VTE risk factors in an individual patient. These risk stratification scores, such as the Rogers score¹⁵ and Caprini score,¹⁶ provide individual patient risk stratification and recommendations for prophylactic anticoagulation. The ninth edition of the American College of Chest Physicians (ACCP) Guidelines for Prevention of VTE in ­Non-Orthopedic Surgical Patients acknowledges both the Rogers and Caprini scores and provides recommendations for VTE prophylaxis (Table 24-3). Orthopedic surgical patients are generally excluded from risk assessment scores because of the disproportionately increased risk of VTE in orthopedic surgery compared with the general and abdominopelvic surgery population.

Diagnosis

Clinical Evaluation

Early in the course of DVT development, venous thrombosis is thought to begin in an area of relative stasis, such as a soleal sinus vein or immediately downstream of the cusps of a venous valve in the axial calf veins. Isolated proximal DVT without tibial vein thrombosis is unusual. Early in the course of a DVT, there may be no or few clinical findings such as pain or swelling. Even extensive DVT may sometimes be present without signs or symptoms. History and physical examination are therefore unreliable in the diagnosis of DVT. In addition, symptoms and signs generally associated with DVT, such as extremity pain and/or swelling, are nonspecific. In large studies, DVT has been found by venography or DUS in ≤50% of patients in whom it was clinically suspected.^17,18 Objective studies are therefore required to confirm a diagnosis of VTE or to exclude the presence of VTE.

Clinical symptoms may worsen as DVT propagates and involves the major proximal deep veins. Extensive DVT of the major axial deep venous channels of the lower extremity with relative sparing of collateral veins causes a condition called phlegmasia cerulea dolens (Fig. 24-4). This condition is characterized by pain and pitting edema with associated cyanosis. When the thrombosis extends to the collateral veins, massive fluid sequestration and more significant edema ensue, resulting in a condition known as phlegmasia alba dolens.¹⁹ The affected extremity in phlegmasia alba dolens is extremely painful and edematous and pale secondary to arterial insufficiency from dramatically elevated below lower knee compartment pressures. Both phlegmasia cerulean dolens and phlegmasia alba dolens can be complicated by venous gangrene and the need for amputation.

Vascular Lab and Radiologic Evaluation

Duplex Ultrasound

DUS is now the most commonly performed test for the detection of infrainguinal DVT, both above and below the knee, and has a sensitivity and specificity of >95% in symptomatic patients.³ DUS refers to the combination of real-time B-mode ultrasound with pulsed Doppler capability. For VTE detection, color flow imaging is an extremely useful adjunct in the evaluation of possible calf vein DVT and evaluation of intra-abdominal veins. DUS provides the ability to noninvasively visualize venous anatomy, detect occluded and partially occluded venous segments, and demonstrate physiologic flow characteristics using a mobile self-contained device.

In the supine patient, normal lower extremity venous flow is phasic (Fig. 24-5), decreasing with inspiration in response to increased intra-abdominal pressure with the descent of the diaphragm and then increasing with expiration as the diaphragm rises and intra-abdominal pressure decreases. When the patient is upright, the decrease in intra-abdominal pressure with expiration cannot overcome the hydrostatic column of pressure existing between the right atrium and the calf. Muscular contractions of the calf, along with the one-way venous valves, are then required to promote venous return to the heart. Flow also can be increased by leg elevation or compression and decreased by sudden elevation of intra-abdominal ­pressure (Valsalva maneuver). In a venous DUS examination performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to Valsalva maneuver are all assessed. From the common femoral through the popliteal vein, the primary method of detecting DVT with ultrasound is demonstration of the lack of compressibility of the vein with probe pressure on B-mode imaging. Normally, in transverse section, the vein walls should coapt with pressure. Lack of coaptation indicates thrombus. Calf vein thrombi are often best detected by abnormalities in color flow imaging.

The examination begins at the ankle and continues proximally to the groin. Each vein is visualized, and the flow signal is assessed with distal and proximal compression. Lower extremity DVT can be diagnosed by any of the following DUS findings: lack of spontaneous flow (Fig. 24-6), inability to compress the vein (Fig. 24-7), absence of color filling of the lumen by color flow DUS, loss of respiratory flow variation, and venous distention. Again, lack of venous compression on B-mode imaging is the primary diagnostic variable. Several studies comparing B-mode ultrasound to venography for the detection of femoropopliteal DVT in patients clinically suspected to have DVT report sensitivities of >91% and specificities of >97%.^20,21 The ability of DUS to assess isolated calf vein DVT varies greatly, with sensitivities ranging from 50% to 93% and specificities approaching 100%.^22,23

Impedance Plethysmography

Impedance plethysmography (IPG) was the primary noninvasive method of diagnosing DVT before the widespread use of DUS but is infrequently used today. Changes in electrical resistance resulting from lower extremity blood volume changes are quantified. IPG is less accurate than DUS for the detection of proximal DVT, with 83% sensitivity in symptomatic patients. It is a poor detector of calf vein DVT.²⁴

Iodine-125 Fibrinogen Uptake

 Iodine-125 fibrinogen uptake (FUT) is a seldom used technique that involves IV administration of radioactive fibrinogen and monitoring for increased uptake in fibrin clots. An increase of 20% or more in one area of a limb indicates an area of thrombus. FUT can detect DVT in the calf, but high background radiation from the pelvis and the urinary tract limits its ability to detect proximal DVT. It also cannot be used in an extremity that has recently undergone surgery or has active inflammation. In a prospective study, FUT had a sensitivity of 73% and specificity of 71% for identification of DVT in a group of symptomatic and asymptomatic patients.²⁵ Currently, FUT is primarily a research tool of historic interest.

Venography

Venography is the gold standard to which other diagnostic modalities are compared. A small catheter is placed in a dorsal foot vein with injection of a radiopaque contrast agent. Radiographs are obtained in at least two projections. A positive study result is failure to fill the deep system with passage of the contrast medium into the superficial system or demonstration of discrete filling defects (Fig. 24-8). A normal study result virtually excludes the presence of DVT. In a study of 160 patients with a normal venogram followed for 3 months, only two patients (1.3%) subsequently developed DVT and no patients experienced symptoms of PE.²⁶ Venography is not routinely used in clinical practice due to invasiveness and complication risk. It is still, however, frequently used in research studies evaluating DVT prophylaxis.

Treatment

Once the diagnosis of VTE has been made, antithrombotic therapy should be initiated promptly. If clinical suspicion for VTE is high, it may be prudent to start treatment while the diagnosis is objectively confirmed. The goals of VTE treatment are the prevention of mortality and morbidity associated with PE and the prevention of the postthrombotic syndrome (PTS). Treatment regimens may include antithrombotic therapy, temporary or permanent vena cava filter placement, catheter-directed or systemic thrombolytic therapy, and operative thrombectomy.

Antithrombotic Therapy

Most often, antithrombotic therapy for VTE is initiated with IV or subcutaneous (SC) unfractionated heparin or SC low molecular weight heparin. Fondaparinux, a synthetic pentasaccharide, is sometimes also used as an alternative to heparin to initiate therapy. An oral vitamin K antagonist, usually sodium warfarin, is begun shortly after initiation of IV or SC therapy. Either SC or IV therapy is continued until effective oral anticoagulation with warfarin is achieved as indicated by an international normalized ratio (INR) ≥2 for 24 hours. A minimum of 5 days of heparin or fondaparinux therapy is recommended.²⁷ Recently, the U.S. Food and Drug Administration (FDA) has also approved alternative oral ­anticoagulants for both treatment and prophylaxis for VTE.

Unfractionated heparin (UFH) binds to antithrombin via a specific 18-saccharide sequence. This increases antithrombin activity over 1000-fold. The antithrombin-heparin complex primarily inhibits factor IIa (thrombin) and factor Xa and, to a lesser degree, factors IXa, XIa, and XIIa of the coagulation cascade. In addition, UFH also binds to tissue factor pathway inhibitor, which inhibits the conversion of factor X to Xa, and factor IX to IXa. Finally, UFH catalyzes the inhibition of thrombin by heparin cofactor II via a mechanism independent of ­antithrombin.

UFH therapy is most commonly administered with an initial IV bolus of 80 units/kg. Weight-based UFH dosages have been shown to be more effective than standard fixed boluses in rapidly achieving therapeutic levels.²⁸ The initial bolus is followed by a continuous IV drip at 18 units/kg per hour. The half-life of IV UFH ranges from 45 to 90 minutes and is dose dependent. The level of antithrombotic therapy should be monitored every 6 hours using the activated partial thromboplastin time (aPTT), with the goal range of 1.5 to 2.5 times control values. This should correspond with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL.

Initial anticoagulation with UFH may also be administered SC, although this route is less commonly used. Adjusted-dose therapeutic SC UFH is initiated with 17,500 units, followed by 250 units/kg twice daily, and dosing is adjusted to an aPTT goal range similar to that for IV UFH. Fixed-dose unmonitored SC UFH is started with a bolus of 333 units/kg, followed by 250 units/kg twice daily.²⁹

Hemorrhage is the primary complication of UFH therapy. The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of >2 units of packed red blood cells) is approximately 5% in hospitalized patients undergoing UFH therapy (1% in medical patients and 8% in surgical patients).²⁹ For patients with UFH-related bleeding complications, cessation of UFH is required, and anticoagulation may be reversed with protamine sulfate. Protamine sulfate binds to UFH and forms an inactive salt compound. Each milligram of protamine neutralizes 90 to 115 units of heparin, and the dosage should not exceed 50 mg IV over any 10-minute period. Side effects of protamine sulfate include hypotension, pulmonary edema, and anaphylaxis. Patients with prior exposure to protamine-containing insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established. Protamine administration should be terminated if any side effects occur.

In addition to hemorrhage, heparin also has unique complications. Heparin-induced thrombocytopenia (HIT) results from heparin-associated antiplatelet antibodies (HAAbs) directed against platelet factor 4 complexed with heparin.³⁰ HIT occurs in 1% to 5% of patients being treated with heparin.^31,32 In patients with repeat heparin exposure (such as vascular surgery patients), the incidence of HAAbs may be as high as 21%.³³ HIT occurs most frequently in the second week of therapy and may lead to disastrous venous or arterial thrombotic complications. Therefore, platelet counts should be monitored periodically in patients receiving continuous heparin therapy.

HIT is diagnosed based on previous exposure to heparin, platelet count less than 100,000, and/or platelet count decline of 50% following exposure. All heparin must be stopped and alternative anticoagulation initiated immediately to avoid thrombotic complications, which may approach 50% over the subsequent 30 days in affected individuals.³⁴

Another complication of prolonged high-dose heparin therapy is osteopenia. Heparin-induced osteopenia results from impairment of bone formation and enhancement of bone resorption by heparin.

Low molecular weight heparins (LMWHs) are derived from the depolymerization of porcine UFH. Like UFH, LMWHs bind to antithrombin via a specific pentasaccharide sequence to expose an active site for the neutralization of factor Xa. However, LMWHs have fewer additional saccharide units. This results in less inactivation of thrombin (factor IIa). In comparison to UFH, LMWHs have increased bioavailability (>90% after SC injection), longer half-lives (approximately 4 to 6 hours), and more predictable elimination rates.

Most patients treated with weight-based once- or twice-daily SC LMWH injections do not require laboratory monitoring for anticoagulant effect, a distinct advantage over continuous IV infusions of UFH. Patients who do require monitoring include those with significant renal insufficiency, pediatric patients, obese patients greater than 120 kg, and pregnant patients. Monitoring may be performed using anti-Xa activity assays. The therapeutic anti-Xa goal range depends on the type of LMWH and the frequency of dosing. There are numerous LMWHs available, and the various preparations differ in their anti-Xa and anti-IIa activities. Treatment dosing for one LMWH therefore cannot be extrapolated for use with another. The anticoagulant effect of LMWHs may be partially reversed (approximately 60%) with protamine sulfate.

Numerous well-designed trials comparing SC LMWH with IV and SC UFH for the treatment of DVT have been critically evaluated in several meta-analyses and demonstrate a decrease in thrombotic complications, bleeding, and mortality with LMWHs.^35,36,37 LMWHs also are associated with a decreased rate of HAAb formation and HIT (<2%) compared with UFH (at least in prophylactic doses).²⁹ However, patients with established HIT also should not receive LMWHs because there is cross-reactivity between the drugs.³⁸

A major benefit of LMWHs is that it allows outpatient treatment of VTE.^39,40 In a randomized study comparing IV UFH and the LMWH nadroparin calcium,³⁹ there was no significant difference in recurrent thromboembolism (8.6% for UFH vs. 6.9% for LMWH) or major bleeding complications (2.0% for UFH vs. 0.5% for LMWH). There was, however, a 67% reduction in mean days in the hospital for the LMWH group.

Fondaparinux currently is a synthetic pentasaccharide that has been approved by the FDA for the initial treatment of DVT and PE. Its five-polysaccharide sequence binds and activates antithrombin, causing specific inhibition of factor Xa. In two large noninferiority trials, fondaparinux was compared with the LMWH enoxaparin for the initial treatment of DVT and with IV UFH for the initial treatment of PE.^41,42 The rates of recurrent VTE ranged from 3.8% to 5%, with rates of major bleeding of 2% to 2.6%, for all treatment arms. The drug is administered SC once daily with a weight-based dosing protocol: 5 mg, 7.5 mg,or 10 mg for patients weighing <50 kg, 50 to 100 kg, or >100 kg, respectively. The half-life of fondaparinux is approximately 17 hours in patients with normal renal function. There are rare case reports of fondaparinux-induced thrombocytopenia.⁴³

Direct thrombin inhibitors (DTIs) include recombinant hirudin, argatroban, and bivalirudin. These antithrombotic agents bind to thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet activation. These actions are independent of antithrombin. The DTIs should be reserved for (a) patients in whom there is a high clinical suspicion or confirmation of HIT, and (b) patients who have a history of HIT or test positive for heparin-associated antibodies. In patients with established HIT, DTIs should be administered for at least 7 days, or until the platelet count normalizes. Warfarin may then be introduced slowly, overlapping therapy with a DTI for at least 5 days.⁴⁴

Bivalirudin is approved primarily for patients with or without HIT who undergo percutaneous coronary intervention and is rarely used outside of that setting.

Commercially available hirudin is manufactured using recombinant DNA technology. It is indicated for the prophylaxis and treatment of patients with HIT. In patients with normal renal function, recombinant hirudin is administered as an IV bolus dose of 0.4 mg/kg, followed by a continuous IV infusion of 0.15 mg/kg per hour. The half-life ranges from 30 to 60 minutes. The aPTT is monitored, starting approximately 4 hours after initiation of therapy, and dosage is adjusted to maintain an aPTT of 1.5 to 2.5 times the laboratory normal value. The less commonly used ecarin clotting time is an alternative method of monitoring. Recombinant hirudin is eliminated via renal excretion, so dosage adjustments are required in patients with renal insufficiency.

Argatroban is indicated for the prophylaxis and treatment of thrombosis in HIT. It also is approved for patients with, or at risk for, HIT undergoing percutaneous coronary intervention. Antithrombotic prophylaxis and therapy are initiated with a continuous IV infusion of 2 μg/kg per minute, without the need for a bolus. The half-life ranges from 39 to 51 minutes, and the dosage is adjusted to maintain an aPTT of 1.5 to 3 times normal. Large initial boluses and higher rates of continuous infusion are reserved for patients with coronary artery thrombosis and myocardial infarction. In these patients, therapy is monitored using the activated clotting time. Argatroban is metabolized and excreted by the liver; therefore, dosage adjustments are needed in patients with hepatic impairment. There is no reversal agent for argatroban.

Vitamin K antagonists, which include warfarin and other coumarin derivatives, are the mainstay of long-term antithrombotic therapy in patients with VTE. Warfarin inhibits the γ-carboxylation of vitamin K–dependent procoagulants (factors II, VII, IX, and X) and anticoagulants (proteins C and S), resulting in formation of less functional proteins. Warfarin usually requires several days to achieve full effect because normal circulating coagulation proteins must first undergo their normal degradation. Factors X and II have the longest half-lives, in the range of 36 and 72 hours, respectively. A steady-state concentration of warfarin is usually not reached for 4 to 5 days.

Warfarin therapy is monitored by measuring the INR, calculated using the following equation:

where ISI is the international sensitivity index. The ISI describes the strength of the thromboplastin that is added to activate the extrinsic coagulation pathway. The therapeutic target INR range is usually 2.0 to 3.0, but the response to warfarin is variable and depends on liver function, diet, age, and concomitant medications. In patients receiving anticoagulation therapy without concomitant thrombolysis or venous thrombectomy, the vitamin K antagonist may be started on the same day as the initial parenteral anticoagulant, usually at doses ranging from 5 to 10 mg. Smaller initial doses may be needed in older and malnourished patients, in those with liver disease or congestive heart failure, and in those who have recently undergone major surgery.⁴⁵

The recommended duration of warfarin antithrombotic therapy is stratified based on whether the DVT was provoked or unprovoked, whether it was the first or a recurrent episode, where the DVT is located, and whether malignancy or thrombophilia is present. Current ACCP recommendations for duration of warfarin therapy are summarized in Table 24-4.

In patients with proximal DVT, several randomized clinical trials have demonstrated that shorter-term antithrombotic therapy (4 to 6 weeks) is associated with a higher rate of VTE recurrence than 3 to 6 months of anticoagulation.^46,47,48 In these trials, most of the patients with transient risk factors had a low rate of recurrent VTE, and most recurrences were in patients with continuing risk factors. The ACCP recommendation, therefore, is that 3 months of anticoagulation are sufficient to prevent recurrent VTE in patients with DVT occurring around the time of a transient risk factor (e.g., hospitalization, orthopedic or major general surgery).

In contrast to patients with thrombosis related to transient risk factors, patients with idiopathic VTE are much more likely to develop recurrence (rates as high as 40% at 10 years). In this latter group of patients, numerous clinical trials have compared 3 to 6 months of anticoagulation therapy with extended-­duration warfarin therapy, both at low intensity (INR of 1.5 to 2.0) and at conventional intensity (INR of 2.0 to 3.0).^49,50,51 In patients with idiopathic DVT, extended-duration antithrombotic therapy is associated with a relative reduction in the rate of recurrent VTE by 75% to >90%. In addition, conventional-intensity ­warfarin reduces the risk even further compared with low-­intensity ­warfarin (0.7 events per 100 person-years vs. 1.9 events per 100 person-years) without an increase in bleeding complications.⁵²

In patients with VTE in association with a hypercoagulable condition, the optimal duration of anticoagulation therapy is influenced more by the clinical circumstances at the time of the VTE (idiopathic vs. secondary) than by the actual presence or absence of the more common thrombophilic conditions. In patients with VTE related to malignancy, increasing evidence suggests that longer-term therapy with LMWH (up to 6 months) is associated with a lower VTE recurrence than treatment using conventional vitamin K antagonists.^53,54 The primary complication of warfarin therapy is hemorrhage, and the risk is related to the magnitude of INR prolongation. Depending on the INR and the presence of bleeding, warfarin anticoagulation may be reversed by (a) omitting or decreasing subsequent dosages, (b) administering oral or parenteral vitamin K, or (c) administering fresh-frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa.⁴⁵

Warfarin therapy rarely may be associated with the development of skin necrosis and limb gangrene. These conditions occur more commonly in women (4:1), and the most commonly affected areas are the breast, buttocks, and thighs. This complication, which usually occurs in the first days of therapy, is occasionally, but not exclusively, associated with protein C or S deficiency and malignancy. Patients who require continued anticoagulation may restart low-dose warfarin (2 mg) while receiving concomitant therapeutic heparin. The warfarin dosage is then gradually increased over a 1- to 2-week period.⁴⁵

Systemic and Catheter-Directed Thrombolysis

Patients with extensive proximal, iliofemoral DVT may benefit from systemic thrombolysis or catheter-directed thrombolysis (CDT). CDT appears to be more effective (see later in chapter) and potentially reduces acute congestive lower extremity symptoms more rapidly than anticoagulation alone and decreases the development of PTS.

Several thrombolytic agents are available, including streptokinase, urokinase, alteplase (recombinant tissue plasminogen activator), reteplase, and tenecteplase. All share the ability to convert plasminogen to plasmin, which leads to the degradation of fibrin. They differ with regard to their half-lives, their potential for inducing fibrinogenolysis (generalized lytic state), their potential for antigenicity, and their FDA-approved indications for use.

Streptokinase is purified from β-hemolytic Streptococcus and is approved for the treatment of acute myocardial infarction, PE, DVT, arterial thromboembolism, and occluded central lines and arteriovenous shunts. It is not specific for fibrin-bound plasminogen, however, and its use is limited by its significant rates of antigenicity. Fevers and shivering occur in 1% to 4% of patients.

Urokinase is derived from human neonatal kidney cells grown in tissue culture. Currently, it is only approved for lysis of massive PE or PE associated with unstable hemodynamics.

Alteplase, reteplase, and tenecteplase all are recombinant variants of tissue plasminogen activator. Alteplase is indicated for the treatment of acute myocardial infarction, acute ischemic stroke, and acute massive PE. However, it often is used for CDT of DVT. Reteplase and tenecteplase are indicated only for the treatment of acute myocardial infarction.

Systemic thrombolysis was evaluated in numerous older prospective and randomized clinical trials, and its efficacy was summarized in a recent Cochrane Review.⁵⁵ In 12 studies involving over 700 patients, systemic thrombolysis was associated with significantly more clot lysis (relative risk [RR] 0.24 to 0.37) and significantly less PTS (RR 0.66). However, venous function was not significantly improved. In addition, more bleeding complications occurred (RR 1.73).

In an effort to minimize bleeding complications and increase efficacy, CDT techniques were developed for the treatment of symptomatic primarily iliofemoral DVT. With catheter-directed therapy, venous access may be achieved through percutaneous catheterization of the ipsilateral popliteal vein, retrograde catheterization through the contralateral femoral vein, or retrograde cannulation from the internal jugular vein. Multi-side-hole infusion catheters, with or without infusion wires, are used to deliver the lytic agent directly into the thrombus. Lytic agents may be administered alone or, now more commonly, in combination with catheter-based methods to physically break up the clot—so-called pharmacomechanical thrombolysis.

The efficacy of CDT for the treatment of symptomatic iliofemoral DVT has been reported in a large multicenter randomized control trial. Two-hundred and nine patients with proximal DVT were assigned to conventional anticoagulant therapy versus conventional anticoagulant therapy plus CDT. In the CDT group, placement of a venous stent was permitted for any identified iliac vein stenotic lesion. At 6 months, iliac vein patency was significantly improved in the thrombolysis group (65.9% vs. 47.4%). At 2 years, in the CDT group, there was an absolute risk reduction of nearly 15% for development of PTS, translating to a number needed to treat of seven patients to prevent one case of PTS.⁵⁶

Inferior Vena Caval Filters

Since the introduction of the Kimray-Greenfield filter in the United States in 1973, numerous vena caval filters have been developed. Although the designs are variable, they all prevent pulmonary emboli, while allowing continuation of venous blood flow through the IVC. Early filters were placed surgically through the femoral vein. Currently, less invasive techniques allow percutaneous filter placement through a femoral vein, internal jugular vein, or small peripheral vein under fluoroscopic or ultrasound guidance.

Placement of an IVC filter is indicated for patients who have manifestations of lower extremity VTE and absolute contraindications to anticoagulation, those that have a bleeding complication from anticoagulation therapy of acute VTE, or those who develop recurrent DVT or PE despite adequate anticoagulation therapy and for patients with severe pulmonary hypertension.

When possible, therapy should be continued in patients with vena cava filters. The duration of anticoagulation is determined by the underlying VTE and not by the presence of the IVC filter itself. Practically speaking, however, many patients who require an IVC filter for recurrent VTE are the same ones who would benefit most from indefinite anticoagulation. In patients who are not able to receive anticoagulants due to recent surgery or trauma, the clinician should continually reassess if anticoagulation may be started safely at a later date.

Placement of permanent IVC filters has been evaluated as an adjunct to routine anticoagulation in patients with proximal DVT.⁵⁷ Routine IVC filter placement has not been shown to prolong early or late survival in patients with proximal DVT but did decrease the rate of PE (hazard ratio, 0.22; 95% confidence interval, 0.05–0.90), however; an increased rate of recurrent DVT was seen in patients with IVC filters (hazard ratio, 1.87; 95% confidence interval, 1.10–3.20).

IVC filters are associated with acute and late complications. Acute complications include thrombosis or bleeding at the insertion site and misplacement of the filter. Late complications include thrombosis of the IVC, DVT, breaking, migration, or erosion of the filter through the IVC (Fig. 24-9). The rate of fatal complications is <0.12%.⁵⁸

In some patients, the need for an IVC filter may be self-limited. Such patients can be treated with so-called removable IVC filters. Depending on the device, removable IVC filters are potentially removable by percutaneous endovascular techniques for up to several months after their initial implantation assuming the filter is no longer required and does not have large amounts of trapped thrombi. All temporary IVC filters are approved for permanent implantation, and many so-called temporary filters end up as permanent devices with all the potential complications of permanent IVC filters.

Operative Venous Thrombectomy

In patients with acute iliofemoral DVT, surgical therapy is generally reserved for patients who worsen with anticoagulation therapy and those with phlegmasia cerulea dolens and impending venous gangrene. If the patient has phlegmasia cerulea dolens, a fasciotomy of the calf compartments is first performed. In iliofemoral DVT, a longitudinal venotomy is made in the common femoral vein and a venous balloon embolectomy catheter is passed through the thrombus into the IVC and pulled back several times until no further thrombus can be extracted. The distal thrombus in the leg is removed by manual pressure beginning in the foot. This is accomplished by application of a tight rubber elastic wrap beginning at the foot and extending to the thigh. If the thrombus in the femoral vein is old and cannot be extracted, the vein may be ligated. For a thrombus that extends into the IVC, the IVC is exposed transperitoneally and controlled below the renal veins. The IVC is opened and the thrombus is removed by gentle massage. An intraoperative completion venogram determines if any residual thrombus or stenosis is present. If a residual iliac vein stenosis is present, intraoperative angioplasty and stenting can be performed. In most cases, an arteriovenous fistula is then created by anastomosing the great saphenous vein (GSV) end to side with the superficial femoral artery in an effort to maintain patency of the thrombectomized iliofemoral venous segment. Heparin is administered postoperatively for several days. Warfarin anticoagulation is maintained for at least 6 months after thrombectomy. Complications of iliofemoral thrombectomy include PE in up to 20% of patients⁵⁹ and death in <1% of patients.⁶⁰

One study followed 77 limbs for a mean of 8.5 years after thrombectomy for acute iliofemoral DVT. In limbs with successful thrombectomy, valvular competence in the thrombectomized venous segment was 80% at 5 years and 56% at 10 years. More than 90% of patients had minimal or no symptoms of PTS. There were 12 (16%) early thrombectomy failures. Patients were required to wear compression stockings for at least 1 year after thrombectomy.⁶¹

Survival rates for surgical pulmonary embolectomy have improved over the past 20 years with the addition of cardiopulmonary bypass. Emergency pulmonary embolectomy for acute PE is rarely indicated. Patients with preterminal massive PE (Fig. 24-10) for whom thrombolysis has failed or who have contraindications to thrombolytics may be candidates for this procedure. Open pulmonary artery embolectomy is performed through a posterolateral thoracotomy with direct visualization of the pulmonary arteries. Mortality rates range between 20% and 40%.^62,63,64

Percutaneous catheter-based techniques for removal of a PE involve mechanical thrombus fragmentation or embolectomy using suction devices. Mechanical clot fragmentation is followed by CDT. Results of catheter-based fragmentation are based on small case series. In a study in which a fragmentation device was used in 10 patients with acute massive PE, fragmentation was successful in 7 patients with a mortality rate of 20%.⁶⁵ Transvenous catheter pulmonary suction embolectomy has also been performed for acute massive PE with a reported 76% successful extraction rate and a 30-day survival of 70%.⁶⁶

Prophylaxis

Patients who undergo major general surgical, gynecologic, urologic, and neurosurgical procedures without thromboprophylaxis have a significant incidence of perioperative DVT. An estimated one third of the 150,000 to 200,000 VTE-related deaths per year in the United States occur following surgery.⁶⁷ The goal of prophylaxis is to reduce the mortality and morbidity associated with VTE. The first manifestation of VTE may be a life-threatening PE (Fig. 24-11), and as indicated earlier, clinical evaluation to detect DVT before PE is unreliable.

Effective methods of VTE prophylaxis involve the use of one or more pharmacologic or mechanical modalities. ­Currently available pharmacologic agents include low-dose UFH, LMWH, synthetic pentasaccharides, and vitamin K antagonists. Mechanical methods include intermittent pneumatic compression (IPC) and graduated compression stockings. There is insufficient evidence to consider aspirin alone as adequate DVT prophylaxis. Methods of prophylaxis vary with regard to efficacy, and the 2012 ACCP Clinical Practice Guidelines stratify their uses according to the patient’s level of VTE risk, bleeding risk, and the values and preferences of individual patients (see Table 24-3).

Venous Thromboembolism Prophylaxis in Nonorthopedic Surgery

The risk for VTE associated with a surgical procedure depends on the type of operation, type of anesthesia, duration of surgery, and other risk factors, such as patient age, presence of cancer, prior VTE, obesity, presence of infection, and known thrombophilic disorders. VTE risk can be stratified according to the previously mentioned risk assessment models, the Caprini score and Rogers score. These risk assessment models are included in the prophylaxis guidelines for nonorthopedic surgery (Tables 24-5 and 24-6). A composite score is created using assigned values for each risk factor. The cumulative score for each patient is then used to predict thrombosis risk and provide recommendations regarding VTE prophylaxis.

Patients at very low risk (<0.5%; Rogers score <7; Caprini score 0) who undergo general or abdominopelvic procedures do not require pharmacologic or mechanical prophylaxis; however, early ambulation is required. Patients at low risk (<1.5%; Rogers score 7–10; Caprini score 1–2) should receive mechanical prophylaxis. Patients at moderate risk (3%; Rogers score >10; Caprini score 3–4) should receive LMWH at recommended doses, low-dose UFH, or mechanical prophylaxis. Patients at high risk (6%; Caprini score ≥5) should receive LMWH at recommended doses or low-dose UFH and mechanical prophylaxis. Thromboprophylaxis should continue until discharge, except in select high-risk patients with malignancy in whom extended-duration prophylaxis (up to 4–6 weeks) may be beneficial. Patients with significant risk for bleeding should receive mechanical prophylaxis until this risk subsides.⁶⁷

Overall, low-dose UFH and LMWH reduce the risk for symptomatic and asymptomatic VTE by 60% to 70%. The risks for bleeding differ, depending on the dosage. Lower dosages of LMWH appear to be associated with less bleeding risk than low-dose UFH, but the latter produces less bleeding risk than higher prophylactic dosages of LMWH.⁶⁸ Other advantages of LMWH include once-daily dosing protocols and a lower rate of heparin-associated antibody formation.

Fondaparinux has been compared with the LMWH dalteparin in patients who undergo high-risk major abdominal surgery. It also has been compared with IPC alone in patients undergoing non–high-risk abdominal surgery.^69,70 Fondaparinux demonstrated rates of VTE prevention, bleeding complications, and mortality similar to those of LMWH. It was more beneficial than IPC alone in reducing VTE but with a higher rate of bleeding (1.6% vs. 0.2%).

Prophylactic insertion of IVC filters has been suggested for VTE prophylaxis in high-risk trauma patients, bariatric surgical patients, and some patients with malignancy who have contraindications for LMWH therapy.⁷¹ A 5-year study of prophylactic IVC filter placement in 132 trauma patients at high risk of PE (head injury, spinal cord injury, pelvic or long bone fractures) reported a 0% incidence of symptomatic PE in patients with a correctly positioned IVC filter.⁷² In 47 patients with a malpositioned IVC filter (strut malposition or filter tilt), there was a 6.3% incidence of symptomatic PE with three deaths. DVT occurred at the insertion site in 3.1% of the patients. IVC patency was 97.1% at 3 years.

Fatal and nonfatal PE can still occur in patients with vena cava interruption. As noted earlier, long-term complications associated with permanent IVC filters include IVC thrombosis and DVT. Currently, the ACCP recommends IVC filters be placed only if a proximal DVT is present and anticoagulation therapy is contraindicated. IVC filter insertion is not recommended for primary prophylaxis.⁶⁷

Removable IVC filters may be placed in patients with a temporarily increased risk of PE.⁷³ The best patient groups for retrievable filter placement may include young trauma patients with transient immobility, patients undergoing surgical procedures associated with a high risk of PE, and patients with hypercoagulable states who cannot receive anticoagulation therapy for a short period of time. Careful follow-up is required to assure all potentially removable filters are in fact removed.

Superficial Vein Thrombophlebitis

Superficial vein thrombophlebitis (SVT) most commonly occurs in varicose veins but can occur in normal veins. When SVT recurs at variable sites in normal superficial veins, thrombophlebitis migrans, it may signify a hidden visceral malignancy or a systemic disorder such as a blood dyscrasia and/or a collagen vascular disease. SVT also frequently occurs as a complication of indwelling catheters, with or without associated extravasation of injected material. Upper extremity vein thrombosis has been reported to occur in 38% of patients with peripherally inserted central catheters; 57% of these developed in the cephalic vein (Fig. 24-12).⁷⁴ Suppurative SVT may occur in veins with indwelling catheters and may be associated with generalized sepsis.

Clinical signs of SVT include redness, warmth, and tenderness along the distribution of the affected veins, often associated with a palpable cord. Patients with suppurative SVT may have fever and leukocytosis. DUS should be performed in patients with signs and symptoms of acute SVT to confirm the diagnosis and to determine if any associated DVT is present. Concomitant lower extremity DVT may be present in 5% to 40% of patients with SVT; most occur in patients with greater saphenous vein SVT within 1 cm of the saphenofemoral junction. A follow-up DUS should be performed in 5 to 7 days in patients with SVT in the proximal GSV but without deep vein involvement. Approximately 10% to 20% of patients with SVT involving the proximal GSV experience progression to deep venous involvement within 1 week.^75,76

Treatment of SVT is quite variable. A Cochrane Review reported that LMWHs and nonsteroidal anti-inflammatory drugs both reduce the rate of SVT extension or recurrence. Topical medications appear to improve local symptoms. Surgical treatment, combined with the use of graduated compression stockings, is associated with a lower rate of VTE and SVT progression.⁷⁷ The treatment is individualized and depends on the location of the thrombus and the severity of symptoms. In patients with SVT not within 1 cm of the saphenofemoral junction, treatment consists of compression and administration of an anti-inflammatory medication such as indomethacin. In patients with suppurative SVT, antibiotics and removal of any existing indwelling catheters are mandatory. Excision of the vein may be necessary but is usually reserved for patients with systemic symptoms or when excision of the involved vein is straightforward. If the SVT extends proximally to within 1 cm of the saphenofemoral junction, extension into the common femoral vein is more likely to occur. In these patients, anticoagulation therapy for 6 weeks and GSV ligation appear equally effective in preventing thrombus extension into the deep venous system.^78,79

Upper Extremity Vein Thrombosis

Axillary-subclavian venous thrombosis (ASVT) is classified into two forms. Primary ASVT occurs in only a small minority of all patients with ASVT. In the primary form, no clear cause for the thrombosis is readily identifiable at initial evaluation. Patients with primary ASVT often give a history of performing prolonged, repetitive motion activities, which results in damage to the subclavian vein, usually where it passes between the head of the clavicle and the first rib in association with the subclavius muscle. This condition is also known as venous thoracic outlet syndrome, effort thrombosis, and Paget-Schroetter syndrome. Secondary ASVT is more common and is associated with an easily identified cause such as an indwelling catheter or a hypercoagulable state. Over 30% of patients with tunneled subclavian vein access devices develop ASVT.⁸⁰

A patient with ASVT may be asymptomatic or may present with varying degrees of upper extremity edema, tenderness, and conspicuous superficial venous enlargement. DUS can be performed initially to confirm the diagnosis, but limitations to the exam by the clavicle and collateralization can lead to a false-negative study. Venography is recommended when there is nonconcordance between the duplex study and clinical suspicion. Anticoagulation therapy should be initiated once ASVT is diagnosed to prevent PE and decrease symptoms.

Treatment of patients with primary upper extremity venous thrombosis is controversial because the natural history of the disease may vary from minimal to no symptoms to significant symptoms with vigorous upper extremity activities. In recent years, patients presenting with acute symptomatic primary ASVT are often considered candidates for CDT therapy with the goal of minimizing long-term symptoms of venous congestion. Venography is performed through a catheter placed using an ultrasound-guided percutaneous basilic vein approach to document the extent of the thrombus (Fig. 24-13). A guidewire is traversed through the thrombus, and a catheter is placed within the thrombus. Typically, tissue plasminogen activator is administered through a multi–side-hole infusion catheter. Various catheter-based mechanical techniques may also be employed to speed thrombus removal. Heparin is administered concurrently with the thrombolytic infusion. After completion of thrombolytic therapy, a follow-up venogram is obtained. Correctable anatomic abnormalities may then be considered for treatment. Adjuvant procedures after thrombolytic therapy may include cervical or first rib resection for thoracic outlet abnormalities, surgical venous reconstruction, and balloon angioplasty of residual venous stenosis.⁸¹

Mesenteric Vein Thrombosis

Five to 15% of cases of acute mesenteric ischemia occur as a result of mesenteric vein thrombosis (MVT). Mortality rates in patients with MVT may approach 50%.⁸² The usual presenting symptom is nonspecific abdominal pain and distention, often accompanied by nausea, vomiting, and diarrhea.⁸³ Peritoneal signs, suggesting intestinal infarction, are present in fewer than half of MVT patients. MVT is more common in patients with a hypercoagulable states, malignancy, and cirrhosis. MVT occurs as a rare complication of laparoscopic surgery.^83,84

Most cases of MVT are diagnosed with contrast-enhanced CT scanning or magnetic resonance imaging (MRI) in the course of an evaluation for abdominal pain. The sensitivity and specificity for CT and MRI approach 100% and 98%, respectively.⁸⁵ Ultrasound can also be used and has reported sensitivity and specificity of 93% and 99%, respectively.

Patients with MVT are treated with fluid resuscitation, heparin anticoagulation, and bowel rest. Once the patient’s ­clinical status improves, oral intake can be carefully started. The patient is transitioned to oral anticoagulation over 3 to 4 days and, depending on the etiology of the MVT, continued for 3 to 6 months or indefinitely. Most patients with MVT can be treated nonoperatively, but urgent laparotomy is indicated in patients with peritoneal findings. Broad-spectrum antibiotics are administered perioperatively. Operative findings consist of edema and cyanotic discoloration of the mesentery and bowel wall. In more advanced cases, thrombus involves the distal mesenteric veins. The arterial supply to the involved bowel is usually intact. Nonviable bowel is resected, and primary anastomosis can be performed. If the viability of the remaining bowel is in question, a second-look operation is performed within 24 to 48 hours.

Varicose veins are common and are present in at least 10% of the general population.⁸⁶ The findings of varicose veins may include dilated and tortuous veins, telangiectasias, and fine reticular varicosities. Risk factors for varicose veins include obesity, female sex, inactivity, and family history.⁸⁷ Varicose veins can be classified as primary or secondary. Primary varicose veins result from intrinsic abnormalities of the venous wall, whereas secondary varicose veins are associated with deep and/or superficial venous insufficiency.

Patients with varicose veins may complain of unsightly appearance, aching, heaviness, pruritus, and early fatigue of the affected leg. These symptoms worsen with prolonged standing and sitting and are relieved by elevation of the leg above the level of the heart. A mild amount of edema is often present. More severe signs include thrombophlebitis, hyperpigmentation, lipodermatosclerosis, ulceration, and bleeding from attenuated vein clusters.

An important component of treatment for patients with varicose veins is the use of elastic compression stockings. Patients may be prescribed elastic stockings with compression ranging from 20 to 30, 30 to 40, or even 40 to 50 mmHg. Stockings range in length from knee high to waist high, and they should cover the symptomatic varices. Elastic compression provides sufficient relief of symptoms in many symptomatic patients.

Cosmetic concerns may lead to intervention. Additionally, interventions are warranted in patients whose symptoms worsen or are unrelieved despite compression therapy or who have lipodermatosclerosis or venous ulcer. Randomized trials of symptomatic patients with varicose veins have demonstrated improved quality of life with interventional treatment. Interventional management includes injection sclerotherapy, surgical therapy, or a combination of both techniques. Injection sclerotherapy alone can be successful in varicose veins <3 mm in diameter and in telangiectatic vessels. Sclerotherapy acts by destroying the venous endothelium. Sclerosing agents include hypertonic saline, sodium tetradecyl sulfate, and polidocanol. Concentrations of 11.7% to 23.4% hypertonic saline, 0.125% to 0.250% sodium tetradecyl sulfate, and 0.5% polidocanol are used for telangiectasias. Larger varicose veins require higher concentrations: 23.4% hypertonic saline, 0.50% to 1% sodium tetradecyl sulfate, and 0.75% to 1.0% polidocanol.⁸³ Elastic bandages are wrapped around the leg after injection and worn continuously for 3 to 5 days to produce apposition of the inflamed vein walls and prevent thrombus formation. After the bandages are removed, elastic compression stockings should be worn for a minimum of 2 weeks. Complications from sclerotherapy include allergic reaction, local hyperpigmentation, thrombophlebitis, DVT, and possible skin necrosis.

Patients with symptomatic GSV or SSV reflux may be treated with endovenous ablation techniques or surgical removal of the affected vein. Endovenous laser and radiofrequency ablation (RFA) techniques have gained in popularity in the past several years. Such techniques are generally associated with more rapid postprocedure recovery than traditional open surgical stripping of the GSV.

With either endoluminal technique, the distal thigh or proximal calf GSV is punctured with a 21-gauge needle under ultrasound guidance. A sheath is placed over a guidewire, and the laser fiber or RFA catheter is advanced until it is near to, but not at, the saphenofemoral junction. Tumescent anesthetic is administered around the GSV, and the vein is treated as the catheter is withdrawn. Endovenous laser treatment and RFA result in durable ablation of the GSV, with rates of varicose vein recurrence and clinical severity scores comparable to those seen with open surgery.^88,89 Risks of endovenous ablation include DVT, ecchymosis, and saphenous nerve injury.

Saphenous vein ligation and stripping is still the more commonly performed procedure worldwide, and it may be the preferred therapy for patients with GSVs of very large diameter (>2 cm). Surgical removal of the GSV usually is performed via small incisions placed medially in the groin and just below the knee. The GSV is removed using a blunt tip catheter or an invagination pin stripper. Complications associated with GSV stripping include ecchymosis, lymphocele formation, DVT, infection, and saphenous nerve injury. GSV stripping is associated with a lower rate of recurrence of varicose veins and a better quality of life than saphenofemoral junction ligation alone.

Larger varicose veins are best treated by surgical excision using the “stab avulsion” technique. Stab avulsions are performed by making 2-mm incisions directly over branch varicosities, and the varicosity is dissected from the surrounding subcutaneous tissue as far proximally and distally as possible through the small incisions (Fig. 24-14). In most cases the vein is simply avulsed with no attempt at ligation. Bleeding is easily controlled with leg elevation, manual compression, and preprocedure tumescent anesthesia.

Chronic venous insufficiency (CVI) affects an estimated 600,000 people in the United States.⁹⁰ Patients complain of leg fatigue, discomfort, and heaviness. Signs of CVI may include varicose veins, pigmentation, lipodermatosclerosis, and venous ulceration. Importantly, severe CVI is not necessarily associated with varicose veins. Chronic venous ulcers carry significant negative physical, financial, and psychological implications. A quality-of-life study reported that 65% of patients with chronic leg ulcers had severe pain, 81% had decreased mobility, and 100% experienced a negative impact of their disease on their work capacity.⁹¹ The socioeconomic impact of chronic venous leg ulcers is staggering, with an estimated 2 million workdays lost per year.⁹² The annual healthcare cost in the United States to treat CVI is estimated at $1 billion.⁹³

CVI can be primary or secondary. Primary CVI results from intrinsic abnormalities of the vein wall, whereas secondary CVI, so-called postthrombotic syndrome (PTS), occurs as a result of DVT. The signs and symptoms of CVI can be therefore be attributed to venous reflux, venous obstruction, calf muscle pump dysfunction, or a combination of these factors, as well as loss of venous wall elasticity.⁹⁴ In the majority of patients with CVI, the most important factor appears to be venous reflux. Venous reflux results from abnormalities of the venous valve. Primary valvular reflux or incompetence is diagnosed when there is no known underlying cause of valvular dysfunction. Secondary valvular reflux is diagnosed when an identifiable cause is present. The most frequent secondary cause is DVT.

Evaluation of Venous Insufficiency

Early diagnostic studies to evaluate CVI required invasive measurements of ambulatory venous pressure (AVP) and venous recovery time (VRT). To measure AVP and VRT, a needle is inserted into a dorsal foot vein and connected to a pressure transducer. The patient is asked to perform 10 tiptoe exercises. Initially there is often a slight upward deflection of pressure with the onset of exercise followed by a decline in pressure with each subsequent tiptoe maneuver. After approximately 10 tiptoes, the measured pressure stabilizes and reflects a balance of venous inflow and outflow. The pressure at this point is the AVP, which is measured in millimeters of mercury. The patient is then asked to stop exercising to allow the vein to fill with return of the venous pressure to baseline. The time required for the venous pressure to return from the AVP level to 90% of baseline pressure is referred to as the VRT. Elevations of AVP indicate venous hypertension. The magnitude of AVP reflects the severity of CVI. There is an 80% incidence of venous ulceration in patients with an AVP of >80 mmHg.⁹⁵

Plethysmography

Noninvasive plethysmography has been used to evaluate CVI. Venous photoplethysmography indirectly evaluates venous function through the use of infrared light. A light-emitting diode is placed just above the medial malleolus, and the patient then performs a series of tiptoe maneuvers. Photoplethysmography provides a measurement of VRT. In limbs with CVI, VRT is shortened compared with that in a normal limb. AVP and VRT are only measures of the overall venous function of a lower extremity venous system. They cannot localize the site of reflux or evaluate the function of the calf pump.

Air plethysmography is a theoretically attractive but not widely used method to assess calf pump function, venous reflux, and overall lower extremity venous function.⁹⁶ An air-filled plastic pressure bladder is placed on the calf to detect volume changes in the leg during a standard set of maneuvers. The patient is first supine and then the leg is elevated and the minimum volume of venous blood recorded. The patient is then asked to assume an upright position with the examined leg non-weight bearing. The venous volume of the examined leg is determined when the volume curve flattens. The venous filling index (VFI), a measure of reflux, is calculated by dividing the maximum venous volume by the time required to achieve maximum venous volume. Next, the patient performs a single tiptoe maneuver, and the ejection fraction (EF) is determined. The EF is the volume change between the recorded volume before and after the tiptoe maneuver and is a measure of calf pump function. At this point, the veins of the leg are allowed to refill. The patient then performs 10 tiptoe maneuvers, and the residual volume fraction is calculated by dividing the venous volume in the leg after 10 tiptoe exercises by the venous volume present before the exercises. The residual volume fraction is a reflection of overall venous function. Theoretically, patients with increased VFIs and normal EFs (indicating the presence of reflux with normal calf pump function) would benefit from antireflux surgery, whereas patients with normal VFIs and diminished EFs would not.

Venous Duplex Ultrasound

Venous DUS has become the gold standard for evaluation of venous function largely supplanting venographic and plethysmographic techniques. The principle advantage of DUS is that it can be used to evaluate reflux in individual venous segments targeting abnormal areas for treatment. The examination has been validated when performed with the patient in the standing position and the examined leg non-weight bearing. Pneumatic pressure cuffs of appropriate size are placed around the thigh, calf, and forefoot. The ultrasound transducer is positioned over the venous segment to be examined, just proximal to the pneumatic cuff (Fig. 24-15). The cuff is then inflated to a standard pressure for 3 seconds and then rapidly deflated. Ninety-five percent of normal venous valves close within 0.5 second.⁹⁷ The presence of reflux for >0.5 second is considered abnormal. Typically, the common femoral, femoral, popliteal, and posterior tibial veins, as well as the GSV and SSV, are evaluated in a complete examination.

Nonoperative Treatment of Chronic Venous Insufficiency

Compression Therapy

Compression therapy is the mainstay of CVI management. Compression can be achieved using a variety of techniques, including elastic compression stockings, paste gauze boots (Unna’s boots), multilayer elastic wraps or dressings (Fig. 24-16), and pneumatic compression devices. Nonelastic compression bandages generally achieve higher and more prolonged degrees of compression than elastic compression bandages. The exact mechanism by which compression therapy can improve CVI remains uncertain. An improvement in skin and subcutaneous tissue microcirculatory hemodynamics as well as a direct effect on subcutaneous pressure have been hypothesized as the mechanisms of efficacy of compression therapy.⁹⁸ Additionally, compression therapy has demonstrated quantifiable differences in ulcer healing with decreases in matrix metalloproteins and inflammatory cytokines.^99,100 Clinically, routine use of elastic and nonelastic bandages reduces lower extremity edema in patients with CVI. In addition, supine perimalleolar subcutaneous pressure has been demonstrated to increase with elastic compression.¹⁰¹ With edema reduction, cutaneous metabolism may improve due to enhanced diffusion of oxygen and other nutrients to the cellular elements of skin and subcutaneous tissues. Increases in subcutaneous tissue pressure with elastic compression bandages may counteract transcapillary Starling forces, which favor leakage of fluid out of the capillary.

Before the initiation of therapy for CVI, patients must be educated about their chronic disease and the need to comply with their treatment plan to heal ulcers and prevent recurrence. A definitive diagnosis of venous ulceration must be made before treatment is initiated. A detailed history should be obtained from a patient presenting with lower extremity ulcerations, including medications used and associated medical conditions that may promote lower extremity ulceration. Arterial insufficiency is assessed by physical examination or noninvasive studies. In addition, systemic conditions that affect wound healing and leg edema, such as diabetes mellitus, immunosuppression, malnutrition, and congestive heart failure, should be improved as much as possible.

Compression therapy is most commonly achieved with graduated elastic compression stockings. Elastic compression stockings are available in various compositions, strengths, and lengths, and can be customized for a particular patient. The benefits of elastic compression stocking therapy for the treatment of CVI and healing of ulcerations have been well documented.^{102,103,104,105} In a retrospective study involving 113 venous ulcer patients,¹⁰³ the use of below-knee, 30- to 40-mmHg elastic compression stockings, after edema and cellulitis were first resolved if present, resulted in 93% healing. Complete ulcer healing occurred in 99 of 102 patients (97%) who were compliant with stocking use vs. 6 of 11 patients (55%) who were noncompliant (P < .0001). The mean time to ulcer healing was 5 months. The rate of ulcer recurrence was lower in patients who were compliant with their compression therapy. By life table analysis, ulcer recurrence was 29% at 5 years for compliant patients and 100% at 3 years for noncompliant patients.

In addition to promoting ulcer healing, elastic compression therapy can also improve quality of life in patients with CVI. In one prospective study,¹⁰⁶ 112 patients with CVI documented by DUS were administered a questionnaire to quantify the symptoms of swelling, pain, skin discoloration, cosmesis, activity tolerance, depression, and sleep alterations. Patients were treated with 30- to 40-mmHg elastic compression stockings. There were overall improvements in symptom severity scores at 1 month after initiation of treatment. Further improvements were noted at 16 months after treatment.

Patient compliance with compression therapy is crucial in treating CVI and especially venous leg ulcers. Many patients are initially intolerant of compression in areas of hypersensitivity adjacent to an active ulcer or at sites of previously healed ulcers. They may also have difficulty applying elastic stockings. To improve compliance, patients should be instructed to wear their stockings initially only as long as it is easily tolerated and then gradually to increase the amount of time the stockings are worn. Alternatively, patients can be fitted with lower-strength stockings initially followed by introduction of higher-strength stockings over a period of several weeks. Many commercially available devices, such as silk inner toe liners, adjustable elastic compression with Velcro, stockings with zippered sides (Fig. 24-17), and metal fitting aids (Fig. 24-18), are available to assist patients in applying elastic stockings. However, despite all these available adjuncts, many patients remain noncompliant with elastic compression therapy.

Another method of compression was developed by the German dermatologist Paul Gerson Unna. Unna’s boot has been used for many years to treat venous ulcers and is available in many versions. A typical Unna’s boot consists of a three-layer dressing and requires application by trained personnel. A rolled gauze bandage impregnated with calamine, zinc oxide, glycerin, sorbitol, gelatin, and magnesium aluminum silicate is first applied with graded compression from the forefoot to just below the knee. The next layer consists of a 4-in-wide continuous gauze dressing followed by an outer layer of elastic wrap, also applied with graded compression. The bandage becomes stiff after drying, and the rigidity may aid in preventing edema formation. Unna’s boot is changed weekly or sooner if the patient experiences significant drainage and soiling of the dressing.

Once applied, Unna’s boot requires minimal patient involvement and provides continuous compression and topical therapy. However, Unna’s boot has several disadvantages. It is bulky and can be uncomfortable, which may affect patient compliance. In addition, the ulcer cannot be monitored after the boot is applied, the technique is labor intensive, and the degree of compression provided is operator dependent. Occasionally, patients may also develop contact dermatitis to the components of Unna’s boot.

The efficacy of Unna’s dressing has been studied. A retrospective 15-year survey encompassing 998 patients with one or more venous ulcers treated weekly with Unna’s dressing¹⁰⁷ reported that 73% of ulcers healed in patients who returned for more than one treatment. The median time to healing for individual ulcers was 9 weeks. Unna’s dressing has been compared to other forms of treatment. A randomized, prospective study¹⁰⁸ comparing Unna’s boot to polyurethane foam dressing in 36 patients with venous ulcers demonstrated superior healing over 12 months in patients treated with Unna’s boot (94.7% vs. 41.2%).¹⁰⁸ A recent Cochrane Review of 39 randomized controlled trials demonstrated that compression increases ulcer healing rates compared with no compression, multicomponent systems are more effective than single-component systems, and multicomponent systems that include an elastic bandage are more effective than those composed mainly of inelastic ­constituents.¹⁰⁹

Other forms of compression dressing available to treat CVI include multilayered dressings and legging orthoses. The purported advantages of multilayered dressings include maintenance of compression for a longer period of time, more even distribution of compression, and better absorption of wound exudates. However, the efficacy of multilayered dressings depends on the wrapping technique of healthcare personnel. A commercially available legging orthosis consisting of multiple adjustable loop-and-hook closure compression bands provides compression similar to that of Unna’s boot and can be applied daily by the patient.¹¹⁰

Skin Substitutes

Several types of skin substitutes are commercially available or under clinical study in the United States.⁹² Bioengineered skin ranges in composition from acellular skin substitutes to partial living skin substitutes. Their mechanism of action in healing venous ulcers is uncertain; however, they may serve as delivery vehicles for various growth factors and cytokines important in wound healing.

Apligraf is a commercially available bilayered living skin construct that closely approximates human skin for use in the treatment of venous ulcers. It contains a protective stratum corneum and a keratinocyte-containing epidermis overlying a dermis consisting of dermal fibroblasts in a collagen matrix.¹¹¹ Apligraf is between 0.5 mm and 1.0 mm thick and is supplied as a disk of living tissue on an agarose gel nutrient medium. It must be used within 5 days of release from the manufacturer¹¹¹ (Fig. 24-19). The disk is easily handled and applied and conforms to irregularly contoured ulcer beds.

A prospective randomized study comparing multilayer compression therapy alone to treatment with Apligraf in addition to multilayered compression therapy has been performed to assess the efficacy of Apligraf in the treatment of venous ulcers.¹⁰⁵ More patients treated with Apligraf had ulcer healing at 6 months (63% vs. 49%, P = .02). The median time to complete ulcer closure was significantly shorter in patients treated with Apligraf (61 days vs. 181 days, P = .003). The ulcers that showed the greatest benefit with the living skin construct were ones that were large and deep (>1000 mm²) or were longstanding (>6 months). No evidence of rejection or sensitization has been reported in response to Apligraf application.

Surgical/Interventional Treatment of Chronic Venous Insufficiency

Perforator Vein Ligation

Incompetence of the perforating veins connecting the superficial and deep venous systems of the lower extremities has been implicated in the development of venous ulcers. The classic open technique described by ­Linton in 1938 for perforator vein ligation has a high incidence of wound complications and has largely been abandoned.¹¹² A minimally invasive technique termed subfascial endoscopic perforator vein surgery (SEPS) evolved with improvement of endoscopic equipment.

DUS is performed preoperatively in patients undergoing SEPS to document deep venous competence and to identify perforating veins in the posterior compartment. The patient is positioned on the operating table with the affected leg elevated at 45° to 60°. An Esmarch bandage and a thigh tourniquet are used to exsanguinate the limb. The knee is then flexed, and two small incisions are made in the proximal medial leg away from areas of maximal induration at the ankle. Laparoscopic trocars are then positioned, and the subfascial dissection is performed with a combination of blunt and sharp dissection. Carbon dioxide is then used to insufflate the subfascial space. The thigh tourniquet is inflated to prevent air embolism. The perforators are then identified and doubly clipped and divided. After completion of the procedure, the leg is wrapped in a compression bandage for 5 days postoperatively.

The efficacy of SEPS as a stand-alone procedure in treatment of venous insufficiency is controversial and unproven. In a report from a large North American registry of 146 patients undergoing SEPS¹¹³ (Fig. 24-20), healing was achieved in 88% of ulcers (75 of 85) at 1 year. Adjunctive procedures, primarily superficial vein stripping, were performed in 72% of patients. Ulcer recurrence was predicted to be 16% at 1 year and 28% at 2 years by life table analysis. These results are similar to those achieved in some studies with compression therapy alone. A review of several studies from 2003 to 2011 demonstrated, when taken in aggregate, that 2059 limbs with 896 ulcers underwent SEPS and concomitant saphenous vein ablation (70%) with a 0% to 16% complication rate and achieved ulcer healing in 90% of patients.¹¹⁴ There has been a multicenter, prospective, European trial performed in patients with venous ulcers to evaluate the efficacy of SEPS. Post hoc analysis suggested possible benefit for SEPS in certain categories of patients with venous ulcer. Overall, however, primary analysis of the study’s end points indicated no advantage to SEPS in addition to superficial venous surgery and compression in the healing of venous ulcers.¹¹⁵ The technique appears to have fallen out of favor in most institutions.

Superficial Venous Surgery

Currently it is accepted that superficial venous surgery in addition to compression therapy has a role in the treatment of patients with venous ulcer. The ESCHAR trial was a randomized prospective trial performed in the United Kingdom to evaluate the combination of superficial venous surgery and compression vs. compression alone in the treatment of venous ulcer. Superficial venous surgery had no additive effect to compression alone in the healing of a venous ulcer but significantly reduced venous ulcer recurrence at 4 years. Based on the results of this trial, it is reasonable to offer ablation or removal of the GSV in addition to compression therapy in patients with abnormal saphenous veins and signs and/or symptoms of severe CVI.¹¹⁶

Deep Venous Valvular Reconstruction

In the absence of significant deep vein valvular incompetence, saphenous vein stripping and possibly perforator vein ligation can be effective in the treatment of CVI. However, in patients with a combination of superficial and deep vein valvular incompetence, the addition of deep vein valvular reconstruction theoretically may improve ulcer healing.¹¹⁷ Numerous techniques of deep vein valve correction have been reported. These techniques consist of repair of existing valves, transplant of venous segments from the arm, transposition of an incompetent vein onto an adjacent competent vein, and implantation of cryopreserved vein segments including competent valves.

Successful long-term outcomes of 60% to 80% have been reported for venous valve reconstructions by internal suture repair.^117,118 However, among patients who initially had ulceration, 40% to 50% still had persistence or recurrence of ulcers in the long term.^115,116

Valve transplantation involves replacement of a segment of incompetent femoral vein or popliteal vein with a segment of axillary or brachial vein with competent valves. Early results are similar to those for venous valve reconstruction.^117,118 However, in the long term, the transplanted venous segments tend to develop incompetence, intimal hyperplasia, and cusp sinus thrombosis with long-term outcomes that are poorer than those for venous valve reconstructions. The outcomes for venous transposition are similar to those for valve transplantation.

Currently, reconstruction techniques for deep venous insufficiency and associated CVI are rarely performed.

Venous Stenting

Currently there is great interest in the role of venous stents in the treatment of CVI. Stenotic lesions of the iliac veins, primarily documented with IVUS, are being reported in a very high percentage of patients with edema, lipodermatosclerosis, or ulceration secondary to venous disease. It appears possible to place percutaneous stents in the iliac veins with near 100% technical success and excellent patency of the stent out to 4 years. Retrospective case series suggest favorable effects on ulcer healing, symptoms of CVI, and quality of life in patients with CVI. The role of venous stenting as a favorable independent procedure in the treatment of patients with CVI remains an area of active investigation.¹¹⁹

Pathophysiology

Lymphedema is extremity swelling that results from a reduction in lymphatic transport and accumulation of lymph within the interstitial space. It is caused by anatomic and or physiologic abnormalities such as lymphatic hypoplasia, functional insufficiency, or absence of lymphatic valves.

The original classification system, described by Allen, is based on the cause of the lymphedema. Primary lymphedema is further subdivided into congenital lymphedema, lymphedema praecox, and lymphedema tarda. Congenital lymphedema may involve a single lower extremity, multiple limbs, the genitalia, or the face. The edema typically develops before 2 years of age and may be associated with specific hereditary syndromes (Turner syndrome, Milroy syndrome, Klippel-Trénaunay-Weber syndrome). Lymphedema praecox is the most common form of primary lymphedema, accounting for 94% of cases. Lymphedema praecox is far more common in women, with the gender ratio favoring women 10:1. The onset is during childhood or the teenage years, and the swelling involves the foot and calf. Lymphedema tarda is uncommon, accounting for <10% of cases of primary lymphedema. The onset of edema is after 35 years of age.

Secondary lymphedema is far more common than primary lymphedema. Secondary lymphedema develops as a result of lymphatic obstruction or disruption. Axillary node dissection leading to lymphedema of the arm is the most common cause of secondary lymphedema in the United States. Other causes of secondary lymphedema include radiation therapy, trauma, infection, and malignancy. Globally, filariasis (an infection caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori) and environmental exposure to minerals in volcanic soil resulting in podoconiosis in barefoot populations are the most common causes of secondary lymphedema.

Clinical Diagnosis

In most patients, the diagnosis of lymphedema can be made based on the history and physical examination alone. Patients commonly complain of heaviness and fatigue in the affected extremity. The limb size increases throughout the day and decreases to some extent over the course of the night when the patient is recumbent. The limb, however, never completely normalizes. In the lower extremity, the swelling classically involves the dorsum of the foot, and the toes have a squared-off appearance. In advanced cases, hyperkeratosis of the skin develops, and fluid weeps from lymph-filled vesicles (Fig. 24-21).

Recurrent cellulitis is a common complication of lymphedema. Repeated infection results in further lymphatic damage, worsening existing disease. The clinical presentation of cellulitis ranges from subtle erythema and worsening of edema to a rapidly progressive soft tissue infection with systemic toxicity.

Many medical conditions can cause edema. If the symptoms are mild, distinguishing lymphedema from other causes of leg swelling can be difficult. Venous insufficiency is often confused with lymphedema. However, patients with advanced venous insufficiency typically have lipodermatosclerosis in the gaiter region, skin ulceration, and/or varicose veins. Bilateral pitting edema is typically associated with congestive heart failure, renal failure, or a hypoproteinemic state.

Radiologic Diagnosis

Duplex Ultrasound

When a patient is evaluated for edema, it is often difficult to distinguish the early stages of lymphedema from venous insufficiency. DUS of the venous system can determine if there is concomitant venous thrombosis or venous reflux, perhaps contributing to extremity edema. The diagnostic modalities discussed in the following sections have limited use in clinical practice. They are invasive and tedious and rarely change the management of a patient with lymphedema. Most physicians rely on the patient’s history and physical examination alone to make the diagnosis of lymphedema.

Lymphoscintigraphy

Lymphoscintigraphy has become the most commonly used diagnostic test to identify lymphatic abnormalities. It has largely replaced lymphangiography. A radiolabeled sulfur colloid (technetium 99m sulfur colloid) is injected into the subdermal, interdigital region of the affected limb. The lymphatic transport is monitored with a whole-body gamma camera, and major lymphatics and nodes can be visualized (Fig. 24-22). In normal individuals, tracer activity may be detected in the inguinal region within 15 to 60 minutes. Within 3 hours, uptake should be present in the pelvic and abdominal lymph nodes. In patients with lymphedema, various patterns may be seen on lymphoscintigraphy. There may be delayed or absent transport to the inguinal nodes. Increased cutaneous collaterals may be seen with obstruction of the primary axial channels. There may be localized regions of reduced uptake in patients with prior node dissection or radiation therapy.

Lymphangiography

Radiologic lymphangiography is performed by first visualizing the lymphatics by injecting colored dye into the hand or foot. The visualized lymphatic segment is exposed through a small incision and cannulated with a 27- to 30-gauge needle. An oil-based dye is then injected slowly into the lymphatics over several hours. The lymphatic channels and nodes are then visualized with traditional radiographs (Figs. 24-23 and 24-24). Lymphangiography is reserved for patients with lymphangiectasia or lymphatic fistulas, and patients who are being considered for microvascular reconstruction.

Management

An important aspect of the management of lymphedema is patient understanding that there is no cure for lymphedema. The primary goals of treatment are to minimize swelling and to prevent recurrent infections. Controlling the chronic limb swelling can improve discomfort, heaviness, and tightness, and potentially reduce the progression of disease.¹²⁰

Compression Garments

Graded compression stockings are widely used in the treatment of lymphedema. The stockings reduce the amount of swelling in the involved extremity by decreasing edema accumulation while the extremity is dependent. When worn daily, compression stockings have been associated with long-term maintenance of reduced limb circumference.¹²¹ They may also protect the tissues against chronically elevated intrinsic pressures, which lead to thickening of the skin and subcutaneous tissue.¹²² Compression stockings also offer a degree of protection against external trauma that may lead to cellulitis.

The amount of compression required for controlling lymphedema ranges from 20 to 60 mmHg and varies among patients. The stockings can be custom made or prefabricated and are available in above- and below-knee lengths. The stockings should be worn during waking hours. The garments should be replaced approximately every 6 months when they lose elasticity.

Bedrest and Leg Elevation

Elevation is an important aspect of controlling lower extremity swelling and is often the first recommended intervention. However, continuous elevation throughout the day can interfere with quality of life more than lymphedema itself. Elevation is an adjunct to lymphedema therapy but is not the mainstay of treatment.

Intermittent Pneumatic Compression Therapy

The use of IPC with a single-chamber or multichamber pump temporarily reduces edema and provides another adjunct to the use of compression stockings. These devices have been shown to be effective in reducing limb volume; however, use of compression stockings is necessary to maintain the volume reduction when the patient is no longer supine because fluid transport is not associated with the transport of macromolecules (proteins) from the tissue. Typically, IPC is used for 4 to 6 hours per day at home when the patient is supine with pressure ranges between 30 and 60 mmHg demonstrated to be most effective.¹²³

Lymphatic Massage

Manual lymphatic drainage is a form of massage developed by Vodder¹²⁴ that is directed at reducing edema. In combination with the use of compression stockings, manual lymphatic drainage is associated with a long-term reduction in edema and fewer infections per patient per year.¹²⁵

Antibiotic Therapy

Patients with lymphedema are at increased risk of developing cellulitis in the affected extremity due to microscopic breakdown in the skin barrier either secondary to swelling or unrecognized and untreated tinea pedis. Recurrent infection can damage the lymphatics, aggravating the edema and increasing the risk for subsequent infection. Staphylococcus and β-hemolytic Streptococcus are the most common organisms causing soft tissue infection. Aggressive antibiotic therapy and elevation with compression are recommended at the earliest signs or symptoms of cellulitis. The drug of choice is penicillin or a cephalosporin active against Streptococcus for 5 days. In patients with recurrent lymphedema despite methods to reduced edema, treatment with monthly intramuscular injections of benzathine penicillin 1.2 MU, twice-daily erythromycin 250 mg, or penicillin V 1 g daily has proven effective at suppression.¹²⁶

Surgery

A variety of surgical procedures have been devised for the treatment of lymphedema. Surgical treatment involves either excision of extra tissue¹²⁷ or anastomosis of a lymphatic vessel to another lymphatic or vein.¹²⁸ In excisional procedures, part or all of the edematous tissue is removed. This does not improve lymphatic drainage but debulks redundant tissue. The microsurgical procedures involve the creation of a lymphaticolymphatic or lymphaticovenous anastomosis, which theoretically improves lymphatic drainage. No long-term follow-up data are available for these interventions, and therefore operative therapy for lymphedema is not well accepted worldwide. Furthermore, operative intervention can further obliterate lymphatic channels, worsening the edema.¹²⁹

Lymphedema is a chronic condition caused by ineffective lymphatic transport, which results in edema and skin damage. Lymphedema is not curable, but the symptoms and long-term effects can be controlled with a combination of elastic compression stockings, limb elevation, pneumatic compression, and massage. Controlling the edema protects the skin and potentially prevents cellulitis.