Disclosure Venous thromboembolic (VTE) disease, the syndrome in which blood clots form in the deep veins and often break loose to travel to the lungs, is one of the most difficult and serious problems in modern medicine. Early recognition and appropriate treatment of deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE) can save many lives. Problem: DVT causes morbidity and mortality both by its behavior in the deep veins and by embolization to the lungs and other parts of the circulation. Because DVT and pulmonary embolism (PE) are a single disease, it is misleading to consider the two conditions separately. Prospective studies in patients with proven DVT but without any signs or symptoms to suggest PE find that roughly half of these "asymptomatic" patients have experienced undiagnosed PE. The more precise the test, the more it appears that virtually every case of DVT embolizes to some extent. With or without PE, DVT itself may be occult. Two thirds of patients with proven PE have no DVT symptoms, and one third of the time it is impossible to find the original site of DVT without an autopsy. All currently available diagnostic tests for DVT are more sensitive and more specific when a patient has lower extremity pain and swelling than when a patient has asymptomatic DVT. All are likely to miss thrombus below the knee or above the groin and are less sensitive for the detection of nonobstructing thrombus than for obstructing thrombus. Frequency: The true prevalence of VTE in the population at large generally is underestimated because most studies depend on the recognition of clinically apparent disease. This approach fails for VTE because many cases are clinically inapparent and because many clinically apparent cases are misdiagnosed. The problem is compounded in retrospective studies, in which incomplete chart notes and inaccurate recollection further cloud clinical certainty. The best epidemiological evidence today comes from the 30-year prospective study of men born in 1913. For every 100,000 person-years, this study found an incidence of 387 cases of recognized venous thrombosis, of which 285 subjects had a diagnosis of PE and 107 had fatal PE. This corresponds to an average of 39 cases and 11 deaths per year in a practice of 10,000 patients. One of every 9 persons develops recognized DVT when younger than 80 years, and clinically recognized VTE accounts for 1 of every 20 deaths in those older than 50 years. Autopsy studies demonstrate that approximately 80% of all cases of DVT and PE remain undiagnosed, even when they are the immediate cause of death. Therefore, the true prevalence in the population at large is probably much higher. Although the prevalence of DVT and PE is highest in patients hospitalized and at bed rest with serious coexisting illnesses, the prevalence in ambulatory outpatients is not insignificant. Emergency department patients whose symptoms include pleuritic chest pain have a rate of PE of 21%. Etiology: A clinical suspicion of DVT or PE often stimulates efforts to identify known risk factors for venous thrombosis. All recognized risk factors for DVT (and thus for PE) arise from the 3 underlying components of the Virchow triad: venous stasis, hypercoagulability, and vessel intimal injury. Although the presence of known risk factors increases the likelihood of PE, the opposite is not true because the absence of occult risk factors cannot be confirmed without an extensive workup. The single most powerful risk marker for DVT is a prior history of VTE. In the absence of prophylaxis, patients who have had prior recognized PE or extensive DVT are virtually certain to develop recurrent VTE with surgery. An increased risk of DVT is also recognized in clinical settings such as the postoperative period, pregnancy, and the puerperium. DVT is common in patients with local trauma and stasis, such as that associated with a leg cast, and in those who smoke, are obese, or travel in confined circumstances (the so-called coach-class syndrome). Other clinical settings commonly reported as risk factors for venous thrombosis are reviewed here. Anesthesia Patients receiving general anesthesia have a 500% increased risk of DVT compared with patients receiving epidural anesthesia for the same surgical procedure. Autoimmune disease and immune deficiency Of patients with systemic lupus erythematosus, 9% develop spontaneous DVT. The lupus anticoagulant responsible for the excess risk is observed in persons with AIDS and in those with many other autoimmune diseases besides lupus and may be induced in healthy patients by phenothiazine drugs. Blood surface antigens Type A blood is associated with lower levels of antithrombin III and higher levels of factor VIII than type O blood. Women of reproductive age with type A blood are 4 times as likely to develop DVT compared with women with type O blood. This association of risk with blood type A does not extend to older men or to women past reproductive age. Cancer Malignancy is an important risk factor for DVT, and spontaneous DVT without an obvious cause is an important marker for possible occult malignancy. In 38% of cases of concomitant cancer and DVT, the DVT is detected first. The relative risk for cancer is 19 times higher for patients younger than 50 years who have had DVT than for those without a history of DVT. Fully 16% of patients with angiographically proven PE are diagnosed with cancer within 2 years. Strokes and neurotrauma DVT is common after stroke or neurological trauma. Without prophylaxis, half the patients develop acute DVT within 5 days following a stroke. Head trauma may cause defibrination, disseminated intravascular coagulation, and DVT. Forty percent of postoperative neurosurgical patients develop DVT. Stroke patients with a single paretic leg develop DVT in 60% of the paralyzed legs but in only 7% of the nonparalyzed ones. Chemotherapy Many types of chemotherapy increase the risk of DVT and PE. Some agents reduce the levels of circulating anticoagulants such as antithrombin III or protein C or S, some cause an increase in circulating procoagulants such as von Willebrand factor, and some depress fibrinolytic activity. Coagulopathy Deficiencies of protein C, protein S, or antithrombin III are well-recognized coagulopathies that together account for approximately 15% of the cases of DVT. Resistance to activated protein C accounts for many more. The lupus anticoagulant is another common coagulopathy that can be inherited or acquired. Patients with familial deficiency of protein C or protein S often experience multiple episodes of DVT or PTE when younger than 35 years. Cancer, chemotherapy, vitamin K deficiency, oral anticoagulant use, surgery, and disseminated intravascular coagulation can trigger an acquired deficiency of protein C. Antithrombin III deficiency may be familial or acquired. Most cases occur in patients with severe liver disease. If antithrombin III levels are reduced to half the normal circulating level, the patient is at high risk for venous thrombosis. More than half the persons with this deficiency experience PTE when younger than 50 years. The most important coagulation abnormality remained completely unrecognized until 1995, when Ridker described a resistance to activated protein C that results from a single point mutation in factor V. This newly recognized hypercoagulable state, known as APC resistance or factor V Leiden, is present in 7% of the general population and is responsible for half the cases of DVT that were previously considered idiopathic. In current practice, any reference laboratory can perform the biological assay for APC resistance, and most can also perform the more accurate DNA test for factor V Leiden. Fibrinolysis Impaired fibrinolysis occurs in several inherited syndromes but is most common in postoperative patients, those taking synthetic estrogens of any type, and women who are pregnant or status postpartum. Heart disease Acute myocardial infarction and congestive heart failure increase the likelihood of DVT and PE, independent of bed rest or immobilization. Patients with acute myocardial infarction who are not receiving anticoagulation have a 26-38% rate of DVT, while similar patients treated for acute myocardial infarction but in whom infarction is eventually excluded have a much lower rate of DVT. Hyperlipidemia The presence of lipemic serum greatly increases the rapidity and extent of thrombus formation in response to vascular injury. Immobility Immobilization that produces stasis is the most important risk factor for DVT and PE. Hospitalized patients should be kept ambulatory whenever possible because DVT occurs in 10% of all patients placed at bed rest in a general medical ward and in 29% of those placed at bed rest in an intensive care unit. Unsuspected PE is a common contributing cause of death in all types of disease. Autopsy findings from patients dying in the hospital from any cause demonstrate PE in 15% of those dying after less than 1 week in the hospital and in 80% of those who die after more prolonged periods of immobilization. Increasing age Increasing age leads to an increased risk of DVT and PE, although whether this is entirely independent of associated factors such as other underlying illness and immobility remains unknown. Inflammatory bowel disease Patients with ulcerative colitis or Crohn disease are at increased risk for DVT and PE because of increased fibrinogen, factor VIII, and platelet activity and depressed levels of antithrombin III and alpha2-macroglobulin. Miscellaneous Homocystinuria and the Shwartzman reaction (ie, immunologic generalized thrombosis) both increase the risk of thromboembolism. Obesity Obesity (weight >20% above ideal weight) has long been accepted as a risk factor for DVT and PE, but the evidence supporting this association is not convincing. When associated factors such as history, illness, immobility, and age are taken into account, obesity may not truly be an independent risk factor. Oral estrogens No published prospective randomized studies have definitively tested and compared the prevalence of DVT or PE in patients taking or not taking oral contraceptives. Case-control and cohort studies based on clinical signs and symptoms of thrombosis suggest a relative risk of approximately 3-12 times higher for patients taking oral contraceptives compared with those not taking them. Polycythemia and thrombocytosis The risk of venous and arterial thrombosis increases linearly with an increasing hematocrit value. Forty percent of deaths in patients with polycythemia vera are related to thrombosis, but only a third of these are due to venous thrombosis. Thrombocytosis may increase or decrease the risk of thrombosis depending on the clinical setting, but platelet counts greater than 1 million most often reduce the likelihood of thrombosis and increase the likelihood of bleeding problems. Pregnancy and puerperium PE is the most common nontraumatic cause of maternal death in pregnancy, and the prevalence is even higher in the postpartum period. In Sweden, 53 peripartum maternal deaths occurred between 1971 and 1980, and 10 of these were due to PTE. Published reports of the incidence of DVT in postpartum patients ranges from 0.61-20 cases per 1000 peripartum months. Prior DVT Patients with a prior episode of DVT are 5 times more likely to develop new DVT compared with patients with no prior episodes of DVT. Prior DVT increases the risk of new postoperative DVT from 26% to 68%. A history of prior clinically apparent PE increases the risk of new postoperative DVT to nearly 100%. Surgery Perioperative DVT can result from minimal venous endothelial injury. The rate of postoperative DVT in patients who do not receive effective prophylaxis is 70% after nonelective hip surgery, 48% percent after elective orthopedic surgery, and 12% after elective general surgery. Approximately one fifth of the cases of postoperative DVT cause a clinically apparent PE, and approximately one third of these are fatal. Even when prophylactic heparin is used, 5-10% of postoperative orthopedic patients develop PE. Nearly half of all deaths in orthopedic surgery patients are due to PE. Tissue antigens HLA antigens Cw4, Cw5, and Cw6 are associated with an increased frequency of DVT and PE. Pathophysiology: Millions of tiny injuries occur within normal blood vessels each day, and millions of tiny microthrombi are formed and lysed in a dynamic balance of functional hemostasis without clinically apparent venous or arterial thrombosis. The German pathologist Virchow demonstrated in 1846 that flow stasis, altered coagulability, or extensive vessel wall injury may cause microthrombi to propagate, resulting in macroscopic thrombi. Vessel wall endothelial damage is the most important of these 3 factors because even minor endothelial injury often results in an accumulation of macroscopic thrombi in the veins. In a sense, thrombus formation at the site of injury is like normal cicatrization of a dermal wound. In a patient with increased coagulation or defective anticoagulation, thrombus formation can be overly exuberant, similar to the formation of a hypertrophic scar. If fibrinolysis is inhibited, the thrombus extends away from the area of the original vascular injury to invade areas of normal endothelium, similarly to keloid formation. Disorders of hemostasis, coagulation, anticoagulation, or fibrinolysis occur in a variety of clinical settings that can cause recurrent DVT or PE and premature arteriosclerotic syndromes or myocardial infarction at an early age. Hemostasis The initiating event in venous thrombosis is platelet adhesion. Even minimal vascular endothelial injury reliably initiates a predictable sequence of events that results in platelet adhesion and thrombus formation. Initial platelet adhesion and aggregation are stimulated by a component of endothelial cells, most likely a substance known as amorphous electron-dense substance, which is exposed by endothelial cell injury. The release of this substance is enhanced by activity of the intrinsic coagulation cascade and is inhibited by platelet antiaggregating agents, thrombolytics, and anticoagulants. Platelet activation causes the release of platelet proaggregants thromboxane A2 and serotonin, resulting in the aggressive recruitment of more circulating platelets to form a hemostatic plug. Thromboxane A2 and serotonin also act to bring about local vasoconstriction. Exposed platelet membrane phospholipids catalyze the activation of factor X and the local (endothelial) formation of thrombin, itself a powerful proaggregant. Thrombin-mediated platelet aggregation is unaffected by aspirin and nonsteroidal anti-inflammatory agents, but aggregation caused by platelet-derived thromboxane A2 is dependent on platelet cyclooxygenase, which is reversibly inhibited by nonsteroidal anti-inflammatory agents and is irreversibly inhibited by aspirin. Coagulation After a hemostatic plug is well established, coagulation pathways are activated and thrombin is generated. Fibrin cross-linking builds a true thrombus out of what was initially a loose aggregation of blood elements. If this series of events were unopposed, any small vascular endothelial injury would result in thrombus propagation throughout the venous system. Three factors serve to retard and prevent uncontrolled propagation: flow dilution, natural anticoagulants, and natural thrombolytics. If blood flow is reduced, activated coagulation factors will accumulate rather than be carried away. If this happens or if some defect is present in the production or function of the natural anticoagulants or thrombolytics, the thrombus forms more vigorously than appropriate for a given vascular injury. The patient develops recurrent venous thrombosis and PTE. Anticoagulation Protein C, protein S, and antithrombin III are the best understood of the natural circulating anticoagulants. Antithrombin III, which interferes with the action of serine proteases such as thrombin, is a general inhibitor of the intrinsic pathway. Protein C (with its cofactor, protein S) inhibits factor V and factor VIII, principal components of the common coagulation pathway. Paradoxically, a functional deficiency of the procoagulant factor V increases resistance to the anticoagulant effects of activated protein C. This deficiency is present in nearly half the patients with clinically recognized venous thrombosis. Many other plasma proteins serve as activators, inhibitors, or cofactors in the coagulation cascade, including such known proteases as heparin cofactor II, alpha2-macroglobulin, alpha1-antitrypsin, and C1 inhibitor. Isolated deficiency of heparin cofactor II can cause recurrent venous thrombosis, and other cofactors can increase the likelihood of thrombosis in response to vascular injury or venous stasis. Together, these plasma proteins prevent minor endothelial injury from initiating uncontrolled intravascular coagulation. Fibrinolysis Fibrinolysis is the body's defense against the formation of a thrombus. Fibrinolysis is initiated by tissue activators and by circulating activators that transform the inactive precursor plasminogen into the active fibrinolytic agent plasmin. Plasmin attacks and degrades fibrin, and when excess plasmin is present, it also attacks and degrades fibrinogen. Damaged endothelial cells release tissue-type plasminogen activator at the same time they bind platelets and initiate the clotting process. This balancing process ensures that under normal conditions, the formation of a thrombus remains localized to an injured area where it is needed. Any disturbance of the delicate balance leads either to increased bleeding or to increased propagation of thrombi. The principal physiologic plasminogen activators are urokinase-type plasminogen activator and tissue-type plasminogen activator. The latter is found in the endothelial cells of vein walls and is released in response to physiologic stimuli such as segmental venous stasis, vessel wall injury, exercise, and the presence of thrombin. Most of the action of tissue-type plasminogen activator occurs at the surface of a thrombus, where plasmin is formed after plasminogen and tissue-type plasminogen activator together bind to fibrin. However, circulating tissue-type plasminogen activator produces a systemic lytic state in which circulating fibrinogen is consumed. Impaired fibrinolytic activity permits thrombus propagation and leads to an increased likelihood of clinically apparent venous thrombosis. Many different problems can interfere with fibrinolysis. Plasminogen levels may be low, or plasminogen may be defective because of structural abnormalities. Fibrinogen and fibrin may be structurally abnormal in such a way as to resist degradation by plasmin. A patient may have high levels of circulating inhibitors of fibrinolysis or low levels of plasminogen activators. Clinical: The clinical diagnosis of DVT is difficult and fraught with uncertainty. The classic signs and symptoms of DVT are those associated with obstruction to venous drainage and include pain, tenderness, and unilateral leg swelling. Other associated nonspecific findings are warmth, erythema, a palpable cord, pain upon passive dorsiflexion of the foot, and spontaneous maintenance of the relaxed foot in abnormal plantar flexion (the Homan sign). When a patient presents with these symptoms, the diagnosis of venous thrombosis is strongly suggested, but no patient should be treated based on clinical findings alone because even when a patient has a swollen, painful, congested leg that appears to be clinically obvious DVT, the chance that DVT is the correct diagnosis is only 50%. Conversely, an absence of signs and symptoms does not rule out DVT. Most cases of DVT lack classic signs or symptoms, and thus, DVT is not considered. Only 7% of postoperative renal transplantation patients, for example, display clinical symptoms of DVT, yet prospective investigation leads to the diagnosis in 20% of cases. DVT simply cannot be diagnosed or excluded based on clinical findings; thus, diagnostic tests must be performed whenever the diagnosis of DVT is being considered. When a patient has DVT, symptoms may be present or absent, unilateral or bilateral, or mild or severe. Thrombus that does not cause a net venous outflow obstruction is often asymptomatic. Thrombus that involves the iliac bifurcation, the pelvic veins, or the vena cava produces leg edema that usually is bilateral rather than unilateral. High partial obstruction often produces mild bilateral edema that is mistaken for the dependent edema of right-sided heart failure, fluid overload, or hepatic or renal insufficiency. Severe venous congestion produces a clinical appearance that can be indistinguishable from the appearance of cellulitis. Patients with a warm, swollen, tender leg should be evaluated for both cellulitis and DVT because patients with primary DVT often develop a secondary cellulitis, while patients with primary cellulitis often develop a secondary DVT. Superficial thrombophlebitis, likewise, is often associated with clinically inapparent underlying DVT. If a patient is thought to have PE or has documented PE, the absence of tenderness, erythema, edema, or a palpable cord upon examination of the lower extremities does not rule out thrombophlebitis, nor does it imply a source other than a leg vein. More than two thirds of patients with proven PTE lack any clinically evident phlebitis. Nearly one third of patients with proven PE have no identifiable source of DVT despite a thorough investigation. Autopsy studies suggest that even when the source is clinically inapparent, it lies undetected within the deep venous system of the lower extremity and pelvis in 90% of cases. DVT below the knee Although DVT below the knee is widely believed to be benign, this is untrue. Most cases of proximal DVT have their origins in the venous sinuses of the calf, and propagation to the popliteal vein and the femoral vein occurs in 20-30% of cases. However, DVT need not spread proximally to cause fatal PE. The single largest autopsy series ever performed to specifically to look for the source of fatal PE was performed by Havig in 1977, who found that one third of the fatal emboli arose directly from the calf veins. The lower leg has 3 principal pairs of deep veins: the anterior tibial vein, draining the dorsum of the foot; the posterior tibial vein, draining the sole of the foot; and the peroneal vein, draining the lateral aspect of the foot. DVT that is isolated to the anterior tibial vein results in PTE in 30% of cases and is responsible for many deaths. Other deep vein groups draining the lower leg include the gastrocnemius plexus and the soleal plexus. These plexuses and the deep venous groups named above all drain via the popliteal vein at the knee. Thrombosis of the popliteal vein results in PTE in 66% of cases, a frequency similar to that of DVT in the thigh. Calf deep vein thrombophlebitis is an important cause of morbidity quite aside from any risk of propagation or of embolization. Isolated calf vein thrombophlebitis results in clinical postphlebitic syndrome in 20-40% of cases. The pathophysiology of the postphlebitic syndrome has been well established as one in which the recanalization of thrombosed deep veins results in the destruction of the venous valves, leading to chronically elevated ambulatory venous pressure within the legs. Valve incompetence need not be extensive to produce venous hypertension and clinical symptoms. Isolated incompetence of the valves in the popliteal segments of the deep venous system leads to elevated ambulatory venous pressures averaging 72 mm Hg, and more than 60% of those with isolated popliteal valve failure develop severe clinical signs of chronic venous insufficiency (CVI). This postphlebitic syndrome is responsible for chronic pain, edema, hyperpigmentation, and ulceration and for many cases of recurrent DVT and PE.
Treatment of some kind is indicated for all patients with DVT.
Relevant Anatomy: Peripheral venous systemThe peripheral venous system functions both as a reservoir to hold extra blood and as a conduit to return blood from the periphery to the heart and lungs. Unlike arteries, which possess 3 well-defined layers (a thin intima, a well-developed muscular media, and a fibrous adventitia), most veins are composed of a single tissue layer. Only the largest veins possess internal elastic membranes, and this layer is thin and unevenly distributed, providing little buttress against high internal pressures. The correct functioning of the venous system depends on a complex series of valves and pumps that are individually frail and prone to malfunction, yet the system as a whole performs remarkably well under extremely adverse conditions. The entire cardiac output volume of 5-10 L/min is received into end-capillary venules for eventual delivery back to the heart and lungs. A large part of this volume passes into the peripheral venous system of the extremities, where it is received against a reverse pressure gradient, then is passed (mostly) uphill against gravity, against fluctuating thoracoabdominal pressures and sometimes in the face of additional back pressures such as the elevated right atrial pressures of congestive heart failure. All of this return circulation occurs with no obvious motive force. Considered in this light, the venous system seems almost magical in its function. Primary collecting veins of the lower extremity are passive thin-walled reservoirs that are tremendously distensible. Most are suprafascial, surrounded by loosely bound alveolar and fatty tissue that is easily displaced. These suprafascial collecting veins can dilate to accommodate large volumes of blood with little increase in back pressure so that the volume of blood sequestered within the venous system at any moment can vary by a factor of 2 or more without interfering with the normal function of the veins. Suprafascial collecting veins belong to the superficial venous system. Outflow from collecting veins is via secondary conduit veins that have thicker walls and are less distensible. Most of these veins are subfascial and are surrounded by tissues that are dense and tightly bound. These subfascial veins belong to the deep venous system. The greater saphenous vein is a superficial vessel that nonetheless lies within a fascial sheath through most of its course from the groin to the ankle. Deep venous systemNo matter what pathway is taken, all venous blood is eventually received by the deep venous system on its way back to the right atrium of the heart. Five major named branches to the deep venous system are found in most patients, 3 below the knee and 2 above the knee. To confuse the issue, the principal deep venous trunk of the leg is called the popliteal vein from below the knee until it passes upward and anteriorly through the adductor canal in the distal thigh, then its name changes to the femoral vein for the remainder of its course in the thigh. Deep veins of the calf The lower leg has 3 groups of deep veins: the anterior tibial vein, draining the dorsum of the foot; the posterior tibial vein, draining the sole of the foot; and the peroneal vein, draining the lateral aspect of the foot. From the ankle, the anterior tibial vein passes upward anterolateral to the interosseous membrane, the posterior tibial vein passes upward posteromedially beneath the medial edge of the tibia, and the peroneal vein passes upward posteriorly through the calf. Venous sinusoids within the calf muscle coalesce to form soleal and gastrocnemius intramuscular venous plexuses, which join the peroneal vein in the mid calf. In most patients, each one of these is actually a pair of veins flanking an artery of the same name, thus there are actually 6 named deep veins below the knee in a typical patient (see Image 2). Just below the knee, the 4 anterior and posterior tibial veins join with the 2 peroneal veins to become the single, large popliteal vein. Deep veins of the thigh The popliteal vein courses proximally behind the knee and then passes anteromedially in the distal thigh through the adductor canal, at which point its name changes to the femoral vein. Importantly, realize that the popliteal vein and the femoral vein are the same vessel and that this is the largest and longest deep vein of the lower extremity. This important deep vein is sometimes incorrectly referred to as the superficial femoral vein in a misguided attempt to distinguish it from the profunda femora, or deep femoral vein, a short, stubby vein that usually has its origin in terminal muscle tributaries within the deep muscles of the lateral thigh but may communicate with the popliteal vein in up to 10% of patients. In the proximal thigh, the femoral vein and the deep femoral vein unite to form the common femoral vein, which passes upwards above the groin crease to become the iliac vein (see Image 2). The misleading and incorrect term superficial femoral vein should never be used because the femoral vein is a deep vein and is not part of the superficial venous system. The incorrect term does not appear in any definitive anatomic atlas, yet it has come into common use in vascular laboratory practice. Confusion arising from use of the inappropriate name has been responsible for many cases of clinical mismanagement and death. Above the thigh The external iliac vein is the continuation of the femoral vein as it passes upward behind the inguinal ligament. At the level of the sacroiliac joint, it unites with the hypogastric vein to form the common iliac vein. The left common iliac is longer than the right and more oblique in its course, passing behind the right common iliac artery. This anatomic asymmetry sometimes results in compression of the left common iliac vein by the corresponding artery to produce May-Thurner syndrome, a left-sided iliac outflow obstruction with localized adventitial fibrosis and intimal proliferation, often with associated DVT. At the level of the fifth lumbar vertebra, the 2 common iliac veins come together at an acute angle to form the inferior vena cava. The calf-muscle pump The passage of blood upward from the feet against gravity depends on a complex array of valves and pumps. Muscle pumps of the calf and thigh provide the motive force for venous return. The most important of these is called the calf-muscle pump, often referred to as the "peripheral heart." The calf-muscle pump is easy to understand by simple analogy to the common hand-pump bulb of a sphygmomanometer. Before pumping has started, the pressure is neutral and equal everywhere throughout the system. When the hand bulb is squeezed, the intake valve is forced closed and the outflow valve is forced open. Air is pumped into the cuff at high pressure. When the hand bulb is allowed to relax, the bulb reexpands. The outflow valve is held closed by high pressure in the cuff, and the intake valve opens to allow refilling of the bulb. Each segment of the calf-muscle pump works in the same way as the hand bulb of the sphygmomanometer. Inflow to a segment of deep vein is through intake valves from perforating veins and from the deep vein segment below. Outflow is through an outflow valve to the deep vein segment above. Squeezing of the vein segment occurs when muscle contraction increases the pressure within a fascial muscle compartment. Like a sphygmomanometer, the calf-muscle pump can achieve pumping pressures of several hundred mm Hg before valve failure occurs. Contraindications: Anticoagulation or fibrinolysis may be relatively or absolutely contraindicated in patients with a particular bleeding risk. Patients with known heparin-induced thrombocytopenia should not receive heparin. |
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Medical therapy: Anticoagulation has been the mainstay of therapy for DVT and PE since the initial introduction of heparin into clinical use in the 1930s. Rapid anticoagulation is essential because thrombus progression and recurrent embolization are 15 times higher in patients who do not receive adequate anticoagulation within the first 48 hours. After initial anticoagulation with heparin, long-term anticoagulation is usually maintained with warfarin. Warfarin should never be started without prior heparinization because warfarin reduces the levels of anticoagulants (eg, protein C and protein S) before it reduces the levels of procoagulant proteins. This produces a hypercoagulable state during the first 5-7 days. If heparin is not given during this period of warfarin induction, many patients have worsening thrombosis. Before 1992, the common practice in Europe was to start patients with DVT directly on warfarin without prior heparinization. This practice was abandoned when Brandjes et al demonstrated in a large randomized prospective trial that the rate of progression of thrombosis and of embolization was 40% when patients were started directly on warfarin, compared with only 8% when full heparin anticoagulation was established before warfarin was started. Intravenous unfractionated heparin is gradually being replaced in modern practice by subcutaneous fractionated low molecular weight heparins. These newer agents offer much easier dosing, a wider therapeutic window, fewer bleeding complications, and faster and more reliable results. Several different preparations are available, but the various heparins are not equivalent and each requires a different dosing regimen. Anticoagulation remains the mainstay of therapy for VTE, but anticoagulation alone is far from adequate therapy for most patients. Anticoagulation can slow or stop the progression of a new thrombus, but it does nothing to remove a thrombus that has already been formed. In many cases, a deep vein thrombus treated by anticoagulation alone fails to recanalize, leaving a chronic obstruction to outflow that is poorly tolerated by the patient. In other cases, the thrombus recanalizes incompletely, leaving a narrowed channel that still produces resistance to outflow. Even when spontaneous recanalization is complete, it usually leaves behind a dysfunctional leg because the thrombus destroys venous valves and produces a valveless channel that leads to profound venous reflux and venous hypertension. For all these reasons, approximately 65% of patients with DVT treated with anticoagulation alone go on to develop a debilitating clinical syndrome of CVI, often referred to as postphlebitic syndrome. This syndrome can include the development of large or small varicose bypass vessels, chronic dermatitis, lipodermatosclerosis, chronic nonhealing ulcers, chronic pain and swelling, an increased incidence of recurrent DVT, and other signs and symptoms of obstructed venous outflow or increased venous reflux. Nearly 90% of patients treated with anticoagulation alone for DVT develop abnormal flow patterns in one or more venous segments, 65% have some degree of whole-leg reflux, and 50% develop clinical signs and symptoms of CVI. Leg ulcers may be seen in up to 80% of patients treated with anticoagulation alone for DVT. Even when the thrombus is isolated to the popliteal segment of the femoral vein, 60% of patients develop clinical CVI if treated with anticoagulation alone. The problem is not confined to patients with lower extremity DVT. Subclavian vein thrombosis treated with anticoagulation alone results in permanent obstruction or CVI in up to 90% of cases. PE occurs in 30% of these cases, and the thrombus extends to occlude the superior vena cava in 10% of cases. Treatment of DVT by fibrinolysis Fibrinolytic therapy has intrinsic appeal because it is intuitively obvious that it is preferable to remove an abnormal clot rather than to allow it to remain in place. Besides the obvious advantage of restoring a widely patent outflow channel, lysis of a thrombus has been demonstrated to preserve and restore normal venous valve structure and function if performed early enough in the course of the disease process. Routine lysis of catheter-associated venous thrombosis has become part of the routine standard of care, partly because catheter-associated femoral, axillary, or subclavian vein thrombosis is often treated by infusion directly into the thrombus through the central venous catheter already in place. Complete lysis of a local thrombus is achieved without a systemic lytic state in the majority of patients in whom direct intrathrombus infusion is possible. The cumulative evidence suggests that compared with anticoagulation alone, lytic therapy for DVT produces more rapid clot resolution, more complete clot resolution, a marked reduction in late symptoms, and a reduced likelihood of recurrent DVT. By removing the clot before venous valve injury occurs, fibrinolysis can maintain and restore normal physiologic function of the venous system of the leg, when anticoagulation alone fails to do so in the vast majority of cases. In most studies, fibrinolysis doubles the likelihood of a normal late venogram and reduces the incidence of symptomatic CVI by 50%. In one study comparing patients receiving only warfarin, heparin plus warfarin, or lytic agents plus warfarin, the incidence of CVI was found to be 80% in the warfarin-only group, 40% in the heparin-warfarin group, and 0% in the lytics-warfarin group. The dose, the agent, and the method of administration used for lytic therapy in published studies vary widely, but in every case, it appears that the greater the reduction in amount of intravenous thrombus and the earlier it can be accomplished, the greater the benefit to the patient. When compared with systemic infusions, transcatheter techniques for delivery of fibrinolytic agents directly into the thrombus have a higher success rate with fewer systemic effects. Catheter-directed fibrinolysis also facilitates monitoring of the progress of fibrinolysis and permits modification of the treatment regimen as needed. Fibrinolysis improves PE mortality and morbidity. Virtually all of the mortality of DVT occurs when fragments of a thrombus embolize to the pulmonary circulation. Anticoagulation can reduce the mortality rate from more than 30% to 10% or less, but this still means that 1 of every 10 patients treated with heparin for PE dies from the disease. Of those who survive a PE and have recurrences, 70% eventually develop chronic pulmonary hypertension because heparin does not dissolve the thrombus that accumulates in the lungs. In 60% of cases, natural fibrinolytic processes eventually recanalize thrombosed pulmonary vessels and restore flow through the area, but the vessels remain lined with a shell of organized fibrous clot. These stiffened vessels have lost their natural elasticity and can no longer perform their normal capacitive volume function. One year after randomization, patients treated with heparin average only 60% of a normal pulmonary capillary volume, while patients randomized to lytic agents have capillary volumes averaging 98% of normal. This stiffening and loss of pulmonary vascular volume in patients treated only with heparin is reflected in the elevated pulmonary vascular resistance and pulmonary artery pressures that are high at rest and become even higher with minimal exercise, even 7 years after the original PE. Patients receiving lytic therapy, on the other hand, have normal pulmonary vascular resistance and normal pulmonary artery pressures both at rest and with exercise. In addition to reduced morbidity, lytic agents markedly reduce the death rate from PE. The original Urokinase Pulmonary Embolism Trials demonstrated that the mortality rate in patients treated with lytic agents was only half that of patients treated with heparin. Although the absolute difference was not statistically significant at the end of the study, it was statistically significant throughout much of the study period. At one point, the survival benefit for lytic therapy was so overwhelming that the investigators actually "broke the code," intending to stop the study if the survival advantage was attributable to heparin rather than to the thrombolytic regimen. Since that time, many small studies and a few larger ones have confirmed that patients with PE treated with lytic agents generally do much better than those treated only with anticoagulants. In one study, 40 hypotensive patients with PE were to be randomized to heparin alone or heparin with fibrinolytics. The study had to be halted after only 8 patients were randomized because all of the patients given heparin had died and none of the patients given fibrinolytic therapy had died. Another study randomized 101 hemodynamically stable patients to heparin or lytic agents. Of the 48 patients who received only heparin, 5 had recurrent PE and 2 died. Of the 55 who were given lytic agents, none had recurrent PE and none died. Finally, a 1997 study by Konstantinides et al, which was a 719-patient multicenter registry study of patients without hypotension but with evidence of right heart strain from PE, showed a mortality rate of 11.1% for patients initially treated with heparin, compared with 4.7% for patients initially treated with fibrinolytic agents (see Image 5). This study found a recurrence rate of 18.7% for heparin but a rate of only 7.7% for lytics. Intracranial bleeds occurred more frequently in the fibrinolytic group, but even when these were added back in, there was an overwhelming advantage for fibrinolysis over heparin, with a total of 11.5% bad outcomes for heparin (11.1% PE deaths + 0.4% strokes) compared with only 5.9% bad outcomes for lytic therapy (4.7% PE deaths + 1.2% strokes). Surgical therapy: Long-term results after DVT are better whenever venous patency and valve function can be established early and maintained. No matter what treatment modality is chosen, preservation of patency and of venous valve function are the strongest predictors of a good long-term outcome. In many patients, fibrinolysis alone is highly effective, and it has become the primary treatment of choice for many forms of venous and arterial thrombosis. Unfortunately, when thrombosis is extensive, fibrinolysis alone may be inadequate to dissolve the volume of thrombus present. Even when the bulk of the thrombus is not excessive, many patients with thrombosis are poor candidates for fibrinolysis because of recent surgery or trauma involving the central nervous system or other noncompressible areas. Venous thrombectomy is a rarely used method of clot extraction that may improve the long-term outcome if it is successful in establishing and maintaining patency. Preoperative details: Precisely defining the location and extent of thrombosis before considering any surgical approach to the problem is important. Duplex ultrasound may sometimes be sufficient for this purpose, but venography (including routine contralateral iliocavography) is a more reliable guide to the anatomy and the particular pathology that must be addressed. Intraoperative details: The patient must be heparinized before the procedure. Traditional venous thrombectomy is performed by surgically exposing and opening the common femoral vein, then threading a Fogarty catheter past the clot, inflating the balloon, and withdrawing it along with the clot. However, care must be taken to avoid dislodging the clot or breaking it into small fragments, because pulmonary embolus will result. A proximal balloon or a temporary caval filter may be used to reduce the likelihood of embolization. Venous valves may sometimes prevent the passage of a catheter in a retrograde direction down the leg. When this happens, the leg may be wrapped tightly with an Esmarch bandage in an attempt to force clot extrusion. Besides traditional balloon thrombectomy, recent developments have produced several new percutaneous mechanical techniques for removal of an acute obstructing thrombus, including angioscopic thromboembolectomy, mechanical disruption thrombectomy, and aspiration thromboembolectomy. Any of these may be performed with or without adjunctive fibrinolytic infusion. Although experience with these newer modalities is limited, each has proven highly effective in the short term, particularly when adjunctive fibrinolysis can be delivered after the clot has been debulked. Some of the mechanical devices available today combine clot maceration with suction removal (eg, AngioJet, Hydrolyser, Oasis), while others (eg, the Amplatz device) use clot maceration alone in a process lightheartedly referred to as "blend and send" thrombectomy. A wide variety of devices are under development or already in release; maceration at the catheter tip can be achieved by use of physical cutting blades, by vortex, by high- or low-pressure saline jets, by suction alone, or by ultrasonic liquefaction. Some of the advantages associated with an angiographic catheter-directed approach to thrombectomy include the use of a percutaneous approach rather than a cutdown on the vessel, reduced risk of perforation when over-the-wire guidance is used, the immediate availability of pretreatment and posttreatment angiography, fluoroscopic localization of catheters, and the ability to dilate and stent an area of stenosis at the same time as the primary thrombectomy (particularly helpful in patients with May-Thurner syndrome). After the thrombus has been removed, construction of a small arteriovenous fistula may assist in maintaining patency by increasing the flow velocity through a thrombogenic iliofemoral venous segment. Postoperative details: To reduce the likelihood of rethrombosis, heparin anticoagulation is usually initiated before surgery, continued during the procedure, and maintained for 6-12 months afterward. Leg compression devices are useful to maintain venous flow. Follow-up care: If thrombosis is associated with an underlying anatomic defect, the defect must be identified and corrected as early as possible after the resolution of the DVT, or the thrombosis will recur. For excellent patient education resources, visit eMedicine's Circulatory Problems Center and Lung and Airway Center. Also, see eMedicine's patient education articles Blood Clot in the Legs, Phlebitis, and Pulmonary Embolism.
Complications of venous thrombectomy include failure to clear the deep venous system, rethrombosis, and PE.
Pooled data from contemporary reports of iliofemoral venous thrombectomy indicate that the early and long-term patency of the iliofemoral venous segment is approximately 80% after thrombectomy but only 30% when patients are treated with anticoagulation alone.
DVT is a life-threatening disease whose conventional treatment has been primarily directed toward inhibiting clot propagation in order to reduce the risk of fatal PE. For the patient who survives an episode of VTE, the potential for long-term sequelae of DVT is often ignored, but chronic obstruction to venous outflow and impaired valve function often result in a syndrome of chronic venous hypertension and postphlebitic syndrome characterized by pain, swelling, varicose veins, hyperpigmentation, skin breakdown, chronic ulceration, and recurrent DVT and PE. The 10-year cost of postphlebitic syndrome, solely in terms of medical expenditures, reportedly exceeds $140,000 per patient. Conventional treatment with anticoagulation has little or no influence on these long-term complications. The past decade has brought significant improvements in the diagnosis and treatment of DVT and PE. A growing body of evidence indicates that for most patients, the benefits of preserved venous patency and preserved valvular competence outweigh the recognized risks of thrombectomy and fibrinolysis. Early clot removal, whether from the deep veins or from the lungs, can restore normal structure and function to these critical parts of the circulatory system. Routine catheter thrombectomy and catheter-directed fibrinolytic therapy are controversial but should now be considered as a potential primary mode of treatment for every patient with VTE.
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