Management of Peripheral Venous Disease
Nancy L. Cantelmo
The scope and prevalence of venous disease in ambulatory practice are considerable, ranging from superficial telangiectasias of cosmetic concern to deep vein thrombosis posing a risk of fatal pulmonary embolization. Early diagnosis is an important task for the primary physician (see Chapter 22); advances in treatment provide enhanced opportunities for outpatient management, by both the primary physician and the vascular specialist. A collaborative approach is often beneficial, necessitating knowledge of the range of treatment options and indications for referral.
PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16)
Normal Physiology
The high frequency of venous disorders of the lower extremities is unique to humans and reflects the consequences of gravity working on an upright posture. To return blood from the periphery to the right heart, the venous system in the legs must work against the force of gravity without the aid of organs specifically designed for this purpose. A number of factors work to lessen venous pressure in the leg and propel blood toward the heart. These include the muscular pump effect of the exercising calf musculature, the negative intrathoracic pressure created by the bellows effect of the chest wall with respiration, and the presence of multiple valves in both superficial and deep venous
systems. The latter prevents reflux of blood and serves to reduce pressure in the veins that would otherwise equal the weight of an uninterrupted column of blood from the heart to the foot (˜100 mm Hg).
systems. The latter prevents reflux of blood and serves to reduce pressure in the veins that would otherwise equal the weight of an uninterrupted column of blood from the heart to the foot (˜100 mm Hg).
Although two venous systems, superficial and deep, are well-known, a third system of perforating veins is less well-recognized, directly connecting the superficial and deep systems. Valves exist in all three systems, maintaining flow from the superficial to the deep system and preventing retrograde flow. When functioning properly, these three systems work in coordinated fashion. The deep intramuscular system, composed of paired anterior and posterior tibial and peroneal veins, popliteal veins, and femoral and deep femoral veins, handles approximately 80% of venous return. The superficial system consists of the great and small saphenous veins and their tributaries. To clarify and standardize venous anatomy, a new nomenclature is now used (Table 35-1).
Clinical disorders of the venous system usually stem from obstruction to venous return due to thrombosis of the vein lumen or from reflux of blood due to incompetent venous valves that allow the retrograde flow of venous blood and persistent elevation of distal venous pressure in the leg and foot.
Varicose Veins
Pathophysiology
The superficial veins lie in the subcutaneous tissue and lack the support afforded by muscle and fascial compartments. Varicose veins are extremely common and affect from 10% to 20% of the adult population to some degree. Women are affected two times as often as men and are also more likely to be symptomatic. A family history of varicosities is present in most patients and lends support to the concept of a hereditary or congenital etiology. Family history, increased age, and female gender are the strongest risk factors for varicose veins. It is unclear whether the primary problem is a congenital incompetence of valves or a weakness of the venous wall itself, which causes dilation of the vein lumen and subsequent valve inadequacy. Remodeling of the extracellular matrix and altered gene expression in response to venous distention and altered shear stress may lead to the disruption of venous architecture. Whatever the causes, a self-perpetuating cycle ensues of venous reflux leading to further vein dilation and valve failure.
In time, the poorly supported superficial veins widen, elongate, and become tortuous. In a smaller percentage of patients, the initial defect may be in the perforating veins, where poorly functioning valves allow abnormal flow toward the superficial system, causing eventual overdistention. In other patients, acquired factors such as lower limb injury or venous thrombosis may play a role. The increased incidence of varicose veins in women implicates hormonal factors, as does the relationship between the duration of hormone replacement therapy and varicose veins. Situations that raise intraluminal vein pressure, such as multiparity and prolonged standing, are also important factors. Pregnancy involves valvular incompetence as well as hormonal factors. Conflicting evidence exists regarding obesity, leg crossing, diet, and abdominal straining as contributing factors to venous disease.
TABLE 35-1 Changes in the Terminology of Venous Anatomy | ||||||||||||||||
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Clinical Presentation
Varicosities most commonly involve the veins of the greater saphenous system and its tributaries and, therefore, occur principally in the medial and anterior thigh, calf, and ankle regions. The small saphenous system may also be involved, producing varicosities of the posterior calf and lateral ankle region. In addition to location, veins are characterized by size. Varicose veins are defined as those greater than 4 mm in diameter and protruding. Reticular veins are smaller than 2 to 4 mm and are usually nonprotruding. Spider veins or telangiectasias are less than 2 mm and are red or purple in color.
Recurrent varices after surgery are a common and complex problem for patients and their physicians, occurring in 20% to 80% of cases. Recognized causes are incomplete surgery with residual refluxing veins, the development of new varicosities from refluxing veins, and neovascularization—the proliferation of blood vessels in tissues not normally containing them.
The presenting symptoms of varicose veins are extremely variable and sometimes bear little relationship to the apparent severity of the varicosities. Complaints are more frequent in women, particularly young women at the time of the menstrual period. Aching is the most commonly reported symptom. Other complaints include cramping, tired legs, and heaviness. Mild swelling is not uncommon, particularly in a leg with particularly severe varicosities, whereas significant swelling would be associated more commonly with deep system problems. Itching is reported particularly over distended veins or associated with an eczema-like rash. Bleeding or ecchymosis may occur, related to trauma or irritation, and may be difficult to control. Phlebitis, limited to the superficial system, presents as a warm, tender, firm, erythematous surface varicosity.
Chronic Venous Insufficiency
Pathophysiology
Chronic venous insufficiency (CVI) can be particularly disabling, causing suffering and significant economic impact. The concept and synonymous term “postphlebitic syndrome” were described by John Homans of Harvard University in 1916. CVI is found twice as often in men as in women. Although the superficial system often contributes to the pathophysiology, the deep and perforating systems assume greater significance in CVI. A documented history of deep venous thrombosis (DVT) can be obtained in less than one half of patients with CVI, but it is believed to be the underlying etiology in most instances. The DVT can often be clinically silent. Despite subsequent recanalization of deep venous occlusions, the phlebitic inflammatory process deforms or destroys venous valves in the deep system, and their incompetence results in reflux and increased venous pressure. Perforating veins undergo similar changes through valvular damage or simply by exposure to chronically elevated pressure from the deep venous system.
In addition to the more common deep and perforator reflux, another, less-well-recognized cause for CVI also exists. Venous outflow obstruction in the iliacaval veins may be responsible for greater than 25 % of CVI. The etiology of this obstruction may be either persistent thrombosis or congenital anatomic obstruction.
In CVI, extravasation of macromolecules and red blood cells is caused by the high venous pressure on the dermal
microcirculation, stimulating an inflammatory response that leads to tissue damage and impedes healing. In addition, reduced local capillary flow and tissue hypoxia further increase tissue breakdown and limit healing. Eventually, these processes and accompanying infection lead to damage of the lymphatics, aggravating the problem.
microcirculation, stimulating an inflammatory response that leads to tissue damage and impedes healing. In addition, reduced local capillary flow and tissue hypoxia further increase tissue breakdown and limit healing. Eventually, these processes and accompanying infection lead to damage of the lymphatics, aggravating the problem.
Clinical Presentation
The hallmarks of CVI are significant edema and skin changes. The edema of CVI is moderate to severe, as differentiated from the milder edema of superficial disease. The edema of CVI usually is improved by elevation, disappearing overnight, as distinguished from lymphedema, which does not resolve. The trophic changes of the skin associated with CVI are hyperpigmentation, lipodermatosclerosis, and active or healed ulceration.
In an effort to provide uniformity in both clinical and research situations, a classification has been developed, much like the TNM (tumor, nodes, metastases) system for cancer. The CEAP classification has four components: C (clinical), E (etiologic), A (anatomic), and P (pathologic). For clinical purposes, the C (clinical) component of the CEAP classification is widely used clearly to convey venous pathology (see Table 35-2).
Deep Vein Thrombophlebitis
Pathophysiology
The cause of acute thrombus formation in the venous system is often unclear, but in most instances, factors contributing to intimal damage, stasis, and hypercoagulability (Virchow triad) comprise the pathophysiologic determinants of venous thrombophlebitis. In about half of instances, the immediate cause is identifiable (e.g., recent orthopedic surgery, immobility, malignancy, a prolonged airplane flight, trauma, pregnancy, estrogen use, previous DVT/PE) or some other acquired factor. Risk is especially pronounced in persons undergoing major orthopedic surgery, in which case the incidence can be as high as 40% to 80%. Although the risk is minimal in healthy persons with no DVT risk factors, the observed incidence of new DVT in persons with a predisposition to DVT who take flights in excess of 6 hours is increased.
In nearly half of cases, no clinical precipitant is evident, leading to the designation idiopathic. Many such cases are now appreciated to have a hereditary or acquired precipitant of DVT. A host of risk factors has been identified (Table 35-3). The emerging pathophysiologic view of idiopathic DVT is that many cases occur in the context of underlying chronic hypercoagulability (either hereditary or acquired) and that a supervening clinical or subclinical event exacerbates the hypercoagulability or causes venous stasis or endothelial injury, triggering acute thrombophlebitis. This view of idiopathic DVT as a chronic disease has important implications for therapy and is supported by the high frequency of recurrent disease, often occurring in a previously unaffected limb.
TABLE 35-2 Clinical Staging of Venous Disease | ||||||||||||||||||
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DVT of the upper extremity has some unique pathophysiologies, typically occurring in young men. Besides trauma from accidents and sports injury, some have abnormalities of the costoclavicular junction compressing and injuring the subclavian vein as part of a thoracic outlet syndrome. Others report repetitive strenuous activity or forceful abduction of the arm prior to onset symptoms resulting in microtrauma to the vein (Paget-Schroetter syndrome). Idiopathic cases probably represent hypercoagulable states, both hereditary and acquired. In older patients, the cause is usually catheter-associated venous injury, cancer, or surgery. Pregnant women and those using oral contraceptives are also at risk.
Hereditary Factors.
An increasing number of hereditary risk factors are being identified. Among the most common is mutation in the gene controlling factor V synthesis, which leads to the production of factor V Leiden, which is resistant to inactivation by the endogenous anticoagulant activated protein C. The factor V variant can be found in 20% of persons with idiopathic first episode DVT and is particularly prevalent among persons of European descent. The thrombotic risk associated with factor V Leiden increases with homozygous status and rises substantially in the context of other risk factors, such as estrogen use. It confers an independent degree of risk that may rise substantially in the context of other risk factors, such as estrogen use. The prothrombin gene mutation, G20210A, is found in only about 5% to 10% of cases, but its presence increases risk by about two to four times more than does factor V Leiden. Deficiencies in the production of proteins that limit clotting to the site of vascular injury (proteins S and C and antithrombin III) are found in about 20% of persons with recurrent DVT. Most patients are heterozygotes for the deficiency, which is a potent risk factor for DVT (Table 35-3).
Acquired Factors.
Major trauma, recent surgery (within 3 months), pregnancy, estrogen use, and immobilization are among the powerful, readily apparent precipitants of acquired causes of DVT. Less evident but no less important are malignancy, heparininduced thrombocytopenia, and the production of antiphospholipid antibodies. There is also an association with atherosclerotic disease. Malignancy, especially adenocarcinoma originating in the lung, gastrointestinal tract, or urogenital system, substantially increases the risk of DVT (by inducing hypercoagulability). Less appreciated is the relationship of occult malignancy to DVT. Among patients presenting with a first case of idiopathic DVT, more than 10% have been found to have an underlying occult malignancy. The risk of developing clinically evident cancer
within 2 years of an episode of idiopathic DVT is estimated at about 8% for a first attack and 17% for recurrent DVT.
within 2 years of an episode of idiopathic DVT is estimated at about 8% for a first attack and 17% for recurrent DVT.
TABLE 35-3 Causes of “Idiopathic” Deep Vein Thrombophlebitis | ||||||||||||||||||||||||||||||||||||
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Antiphospholipid antibodies are believed to induce thrombosis by causing vascular injury or by interacting with other abnormal clotting factors to induce a hypercoagulable state. Two classes of antiphospholipid antibodies have been identified: anticardiolipin and lupus anticoagulant. Both appear to develop in response to prior infection. A secondary antiphospholipid syndrome is seen in persons with systemic lupus erythematosus. Low titers of antiphospholipid antibody can be found in a small proportion of normal persons and in up to 25% of pregnant woman by the end of the first trimester. A sevenfold increase in risk is associated with their production, especially the lupus anticoagulant variety, making this a potent acquired risk factor for DVT.
Homocysteinemia may be associated with kidney failure, cancer, diabetes, liver failure, or deficiencies of folic acid, B6 vitamin, and B12 vitamin. It may also result from a specific gene mutation.
An important predictor of recurrent DVT is residual venous thrombosis. After an initial acute episode of DVT, there is a steady progression of clot organization and recanalization. At 6 months, nearly 40% of patients show no residual clot; by 1 year, the number rises to about 60%, and it peaks at about 75% at 3 years. Those with residual thrombus on ultrasound have 2½ times the risk for recurrence of those without detectable clot.
Clinical Presentation
DVT is notoriously variable and often subtle in its clinical presentation. Unilateral leg edema may be the only finding; it stands out as the most sensitive indicator of DVT. Classically, the patient complains of pain in the limb that is worse with motion, walking, or dependency and better with rest or elevation of the extremity. Leg edema below the level of the clot, pain on compression of the knee, a Homan sign (calf pain produced by dorsiflexion of the foot), and a palpable cord are cited as the classic physical findings but are extremely nonspecific. With extensive DVT, a dusky cyanosis may appear. Unfortunately, most classic findings have proven to be disappointingly low in sensitivity and specificity. A patient reporting little or no pain and showing no calf tenderness may harbor extensive deep venous clots, whereas another with impressive pain, calf tenderness, and an apparently positive Homan sign may be clot-free.
DVT in an upper extremity may present as pain, swelling, paresthesias, and weakness of the arm in conjunction with physical findings of edema, discoloration, and prominent venous collaterals.
Postthrombotic/Postphlebitic Syndrome
More than 30% of persons with symptomatic proximal DVT will develop postthrombotic (postphlebitic) syndrome; most will have mild disease, but over a third will develop moderate or severe symptoms. Onset is usually within 1 year after DVT. Manifestations range from minor discomfort, swelling, heaviness, skin discoloration, and venous ectasia to chronic pain, cramping aggravated by standing or walking, and refractory skin ulceration and edema. Symptoms can have a significant effect on quality of life. Those at risk for poorer long-term outcomes have extensive DVT or more severe postthrombotic signs and symptoms at 1 month after DVT.
Varicose Veins
On physical examination, the extent and location of varicosities in the standing patient should be noted, as well as the presence of edema or skin change. Significant trophic changes are unusual in patients with only superficial venous pathology but are commonly found in those with involvement of both superficial and deep systems. Complaints of leg pain should be carefully evaluated to rule out other possibilities, such as arterial insufficiency, musculoskeletal disorders, and neurologic problems. Severe varicosities occurring at a young age or varicosities after trauma may suggest an arteriovenous connection.
Venous Insufficiency
Venous insufficiency needs to be distinguished from other causes of leg edema such as lymphatic obstruction, hypoalbuminemia, and DVT (see Chapter 22). Any accompanying leg ulcers must be differentiated from those due to arterial insufficiency, which tend to be more “punched out” in appearance and localized to the dorsum or lateral aspect of the foot or ankle. A history of claudication, rest pain relieved by dependency, absent pulses, bruits, dependent rubor, and atrophic skin changes also helps to distinguish arterial disease from venous insufficiency.
Doppler (duplex) ultrasound has become a mainstay of diagnosis of venous disease, varicose veins, CVI, and phlebitis after a thorough history and physical exam. If the patient is symptomatic and has significant signs and symptoms, a duplex exam is warranted.
Most ultrasound laboratories are able to perform adequate examination for DVT or superficial phlebitis; special expertise and patience are needed to perform adequate duplex examination for reflux. A proper duplex exam offers an extensive interrogation of the superficial, deep, and perforating vein systems. The presence of valvular reflux (>0.05 seconds) is best identified with the patient in the standing position with the aid of automated inflation/deflation cuffs.
Superficial Thrombophlebitis
Physical examination should exclude other diagnoses that may be confused with superficial thrombophlebitis, such as cellulitis or lymphangitis. In the last two, there is an absence of a palpable thrombosed vein, widespread distribution of erythema and swelling beyond the course of a vein, and identification of a possible focus of infection. Musculoskeletal and neurologic causes of pain and tenderness should be sought, such as a Baker cyst in the popliteal fossa (see Chapter 152) or radicular pain (see Chapter 147). Swelling of the extremity should also be carefully noted because isolated superficial phlebitis should not contribute to generalized edema. A duplex ultrasound examination is essential in a superficial phlebitis to determine the extent of the phlebitic segment and the proximity or involvement of the deep system.
Deep Vein Thrombophlebitis
The initial evaluation of the patient who complains of unilateral leg edema with or without calf pain must include consideration of DVT (see Chapter 22). Prompt detection of proximal deep vein thrombophlebitis is critical; undetected and untreated, it may lead to pulmonary embolization, with its substantial risk of major cardiopulmonary morbidity and mortality. Identification of DVT in the absence of obvious precipitants raises the question of underlying hypercoagulability and occult malignancy, which needs to be addressed because the results affect the approach to management.
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