Deep Venous Thrombosis (DVT)

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Practice Essentials

Deep venous thrombosis (DVT) is a manifestation of venous thromboembolism (VTE). Although most DVT is occult and resolves spontaneously without complication, death from DVT-associated massive pulmonary embolism (PE) causes as many as 300,000 deaths annually in the United States.[1] See the image below.



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Deep venous thrombosis (DVT). The computed tomography venogram shows bilateral deep venous thrombosis (arrows).

Signs and symptoms

Symptoms of DVT may include the following:

As many as 46% with patients with classic symptoms have negative venograms,[2] and as many as 50% of those with image-documented venous thrombosis lack specific symptoms.[2, 3]

No single physical finding or combination of symptoms and signs is sufficiently accurate to establish the diagnosis of DVT, but physical findings in DVT may include the following:

Potential complications of DVT include the following:

See Clinical Presentation for more detail.

Diagnosis

The American Academy of Family Physicians (AAFP)/American College of Physicians (ACP) recommendations for workup of patients with probable DVT are as follows[5] :

The main laboratory studies to be considered include the following:

See Workup for more detail.

Management

Treatment options for DVT include the following:

Heparin products used in the treatment of DVT include the following:

Factor Xa inhibitors used in the treatment of DVT include the following:

Endovascular therapy is performed to reduce the severity and duration of lower-extremity symptoms, prevent PE, diminish the risk of recurrent VTE, and prevent PTS. Percutaneous transcatheter treatment of DVT includes the following:

American Heart Association (AHA) recommendations for inferior vena cava filters include the following[10] :

See Treatment and Medication for more detail.

Background

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are manifestations of a single disease entity, namely, venous thromboembolism (VTE). The earliest known reference to peripheral venous disease is found on the Eber papyrus, which dates from 1550 BC and documents the potentially fatal hemorrhage that may ensue from surgery on varicose veins. In 1644, Schenk first observed venous thrombosis when he described an occlusion in the inferior vena cava. In 1846, Virchow recognized the association between venous thrombosis in the legs and PE.

DVT is the presence of coagulated blood, a thrombus, in one of the deep venous conduits that return blood to the heart. The clinical conundrum is that symptoms (pain and swelling) are often nonspecific or absent. However, if left untreated, the thrombus may become fragmented or dislodged and migrate to obstruct the arterial supply to the lung, causing potentially life-threatening PE See the images below.



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Deep venous thrombosis (DVT). The image shows venous thrombi.



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Deep venous thrombosis (DVT). A pulmonary embolus is shown.

DVT most commonly involves the deep veins of the leg or arm, often resulting in potentially life-threatening emboli to the lungs or debilitating valvular dysfunction and chronic leg swelling. Over the past 25 years, the pathophysiology of DVT has become much better understood, and considerable progress has been made in its diagnosis and treatment.

DVT is one of the most prevalent medical problems today, with an annual incidence of 80 cases per 100,000. Each year in the United States, more than 200,000 people develop venous thrombosis; of those, 50,000 cases are complicated by PE.[11] Lower-extremity DVT is the most common venous thrombosis, with a prevalence of 1 case per 1000 population. In addition, it is the underlying source of 90% of acute PEs, which cause 25,000 deaths per year in the United States (National Center for Health Statistics [NCHS], 2006).

Conclusive diagnosis has historically required invasive and expensive venography, which is still considered the criterion standard. The diagnosis may also be obtained noninvasively by means of ultrasonographic examination. (See Workup.)

Early recognition and appropriate treatment of DVT and its complications can save many lives. (See Treatment and Management.) The goals of pharmacotherapy for DVT are to reduce morbidity, prevent postthrombotic syndrome (PTS), and prevent PE. The primary agents include anticoagulants and thrombolytics. (See Medication.)

Other than the immediate threat of PE, the risk of long-term major disability from postthrombotic syndrome is high.[12, 13, 14, 15, 16]

For patient education resources, see the Lung Disease & Respiratory Health Center, as well as the patient education articles Deep Vein Thrombosis (Blood Clot in the Leg, DVT), Phlebitis, and Pulmonary Embolism.

Anatomy

The 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.

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, through which all venous blood must eventually pass through on its way back to the right atrium of the heart. The lower limb deep venous system is typically thought of as 2 separate systems, one below the knee and one above.

The calf has 3 groups of paired deep veins: the anterior tibial veins, draining the dorsum of the foot; the posterior tibial veins, draining the sole of the foot; and the peroneal veins, draining the lateral aspect of the foot. Venous sinusoids within the calf muscle coalesce to form soleal and gastrocnemius intramuscular venous plexuses, which join the peroneal veins in the mid calf. These veins play an important role in the muscle pump function of the calf. Just below the knee, these tibial veins join to become the popliteal vein, which too can be paired on occasion.

Together, the calf’s muscles and deep vein system form a complex array of valves and pumps, often referred to as the “peripheral heart,” that functions to push blood upward from the feet against gravity. The calf-muscle pump is analogous to the common hand-pump bulb of a sphygmomanometer filling a blood pressure cuff. Before pumping has started, the pressure is neutral and equal everywhere throughout the system and the calf fills with blood, typically 100-150 mL. When the calf contracts, the feeding perforator vein valves are forced closed and the outflow valves are forced open driving the blood proximally. When the calf is allowed to relax, the veins and sinusoids refill from the superficial venous system via perforating veins, and the outflow valve is then forced shut, preventing retrograde flow. With each “contraction,” 40-60% of the calf’s venous volume is driven proximally.[17]

The deep veins of the thigh begin distally with the popliteal vein as it courses proximally behind the knee and then passes through the adductor canal, at which point its name changes to the femoral vein. (This important deep vein is sometimes incorrectly referred to as the superficial femoral vein in a misguided attempt to distinguish it from the profunda femoris, 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.

The term superficial femoral vein should never be used, because the femoral vein is in fact a deep vein and is not part of the superficial venous system. This 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.) In theproximal 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.

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 right common iliac artery to produce May-Thurner syndrome, a left-sided iliac outflow obstruction with localized adventitial fibrosis and intimal proliferation, often with associated deep venous thrombosis. 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.

Please go to the main article on Inferior Vena Caval Thrombosis for more information.

Pathophysiology

Over a century ago, Rudolf Virchow described 3 factors that are critically important in the development of venous thrombosis: (1) venous stasis, (2) activation of blood coagulation, and (3) vein damage. These factors have come to be known as the Virchow triad.

Venous stasis can occur as a result of anything that slows or obstructs the flow of venous blood. This results in an increase in viscosity and the formation of microthrombi, which are not washed away by fluid movement; the thrombus that forms may then grow and propagate. Endothelial (intimal) damage in the blood vessel may be intrinsic or secondary to external trauma. It may result from accidental injury or surgical insult. A hypercoagulable state can occur due to a biochemical imbalance between circulating factors. This may result from an increase in circulating tissue activation factor, combined with a decrease in circulating plasma antithrombin and fibrinolysins.

Over time, refinements have been made in the description of these factors and their relative importance to the development of venous thrombosis. The origin of venous thrombosis is frequently multifactorial, with components of the Virchow triad assuming variable importance in individual patients, but the end result is early thrombus interaction with the endothelium. This interaction stimulates local cytokine production and facilitates leukocyte adhesion to the endothelium, both of which promote venous thrombosis. Depending on the relative balance between activated coagulation and thrombolysis, thrombus propagation occurs.

Decreased vein wall contractility and vein valve dysfunction contribute to the development of chronic venous insufficiency. The rise in ambulatory venous pressure causes a variety of clinical symptoms of varicose veins, lower extremity edema, and venous ulceration.

Development of thrombosis

Thrombosis is the homeostatic mechanism whereby blood coagulates or clots, a process crucial to the establishment of hemostasis after a wound. It may be initiated via several pathways, usually consisting of cascading activation of enzymes that magnify the effect of an initial trigger event. A similar complex of events results in fibrinolysis, or the dissolution of thrombi. The balance of trigger factors and enzymes is complex. Microscopic thrombus formation and thrombolysis (dissolution) are continuous events, but with increased stasis, procoagulant factors, or endothelial injury, the coagulation-fibrinolysis balance may favor the pathologic formation of an obstructive thrombus. Clinically relevant deep venous thrombosis is the persistent formation of macroscopic thrombus in the deep proximal veins.

For the most part, the coagulation mechanism consists of a series of self-regulating steps that result in the production of a fibrin clot. These steps are controlled by a number of relatively inactive cofactors or zymogens, which, when activated, promote or accelerate the clotting process. These reactions usually occur at the phospholipid surface of platelets, endothelial cells, or macrophages. Generally, the initiation of the coagulation process can be divided into 2 distinct pathways, an intrinsic system and an extrinsic system (see the image below).



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Deep venous thrombosis (DVT). The coagulation pathway is shown.

The extrinsic system operates as the result of activation by tissue lipoprotein, usually released as the result of some mechanical injury or trauma. The intrinsic system usually involves circulating plasma factors. Both of these pathways come together at the level of factor X, which is activated to form factor Xa. This in turn promotes the conversion of prothrombin to thrombin (factor II). This is the key step in clot formation, for active thrombin is necessary for the transformation of fibrinogen to a fibrin clot.

Once a fibrin clot is formed and has performed its function of hemostasis, mechanisms exist in the body to restore the normal blood flow by lysing the fibrin deposit. Circulating fibrinolysins perform this function. Plasmin digests fibrin and also inactivates clotting factors V and VIII and fibrinogen.

Three naturally occurring anticoagulant mechanisms exist to prevent inadvertent activation of the clotting process. These include the heparin-antithrombin III (ATIII), protein C and thrombomodulin protein S, and the tissue factor inhibition pathways. When trauma occurs, or when surgery is performed, circulating ATIII is decreased. This has the effect of potentiating the coagulation process. Studies have demonstrated that levels of circulating ATIII is decreased more, and stay reduced longer, after total hip replacement (THR) than after general surgical cases (see the image below).



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Deep venous thrombosis (DVT). This chart shows postoperative antithrombin III levels.

Furthermore, patients who have positive venograms postoperatively tend to be those in whom circulating levels of ATIII are diminished (see the image below).



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Deep venous thrombosis (DVT). This chart depicts perioperative antithrombin III levels and DVT formation.

Under normal circumstances, a physiologic balance is present between factors that promote and retard coagulation. A disturbance in this equilibrium may result in the coagulation process occurring at an inopportune time or location or in an excessive manor. Alternatively, failure of the normal coagulation mechanisms may lead to hemorrhage.

Thrombus usually forms behind valve cusps or at venous branch points, most of which begin in the calf. Venodilation may disrupt the endothelial cell barrier and expose the subendothelium. Platelets adhere to the subendothelial surface by means of von Willebrand factor or fibrinogen in the vessel wall. Neutrophils and platelets are activated, releasing procoagulant and inflammatory mediators. Neutrophils also adhere to the basement membrane and migrate into the subendothelium. Complexes form of the surface of platelets and increase the rate of thrombin generation and fibrin formation. Stimulated leukocytes irreversibly bind to endothelial receptors and extravasate into the vein wall by means of mural chemotaxis. Because mature thrombus composed of platelets, leukocytes and fibrin develops, and an active thrombotic and inflammatory process occurs at the inner surface of the vein, and an active inflammatory response occurs in the wall of the vein.[18, 19]

Studies have shown that low flow sites, such as the soleal sinuses, behind venous valve pockets, and at venous confluences, are at most risk for the development of venous thrombi.[20, 21] However, stasis alone is not enough to facilitate the development of venous thrombosis. Experimental ligation of rabbit jugular veins for periods of up to 60 minutes have failed to consistently cause venous thrombosis.[22, 23] Although, patients that are immobilized for long periods of time seem to be at high risk for the development of venous thrombosis, an additional stimulus is required to develop deep venous thrombosis (DVT).

Evolution of venous insufficiency

Over time, thrombus organization begins with the infiltration of inflammatory cells into the clot. This results in a fibroelastic intimal thickening at the site of thrombus attachment in most patients and a fibrous synechiae in up to 11%.[24] In many patients, this interaction between vessel wall and thrombus leads to valvular dysfunction and overall vein wall fibrosis. Histological examination of vein wall remodeling after venous thrombosis has demonstrated an imbalance in connective tissue matrix regulation and a loss of regulatory venous contractility that contributes to the development of chronic venous insufficiency.[25, 26] Some form of chronic venous insufficiency develops in 29-79% of patients with an acute DVT, while ulceration is noted in 4-6%.[27, 28] The risk has been reported to be 6 times greater in those patients with recurrent thrombosis.[29]

Over a few months, most acute DVTs evolve to complete or partial recanalization, and collaterals develop (see the images below).[30, 31, 32, 33, 34, 35] Although blood flow may be restored, residual evidence of thrombus or stenosis is observed in half the patients after 1 year. Furthermore, the damage to the underlying valves and those compromised by peripheral dilation and insufficiency usually persists and may progress. Venous stasis, venous reflux, and chronic edema are common in patients who have had a large DVT.[36]



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Deep venous thrombosis (DVT). This lower-extremity venogram shows outlining of an DVT in the popliteal vein with contrast enhancement.



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Deep venous thrombosis (DVT). The lower-extremity venogram reveals a nonocclusive chronic thrombus. The superficial femoral vein (lateral vein) has th....

The acute effect of an occluded outflow vein may be minimal if adequate collateral pathways exist. As an alternative, it may produce marked pain and swelling if flow is forced retrograde. In the presence of deep vein outflow obstruction, contraction of the calf muscle produces dilation of the feeding perforating veins, it renders the valves nonfunctional (because the leaflets no longer coapt), and it forces the blood retrograde through the perforator branches and into the superficial system. This high-pressure flow may cause dilation of the superficial (usually low-pressure) system and produce superficial venous incompetence. In clinical terms, the increased incidence of reflux in the ipsilateral greater saphenous vein increases 8.7-fold on follow-up of DVT.[30] This chain of events (ie, obstruction to antegrade flow producing dilation, stasis, further valve dysfunction, with upstream increased pressure, dilation, and other processes) may produce hemodynamic findings of venous insufficiency.

Another mechanism that contributes to venous incompetence is the natural healing process of the thrombotic vein. The thrombotic mass is broken down over weeks to months by inflammatory reaction and fibrinolysis, and the valves and venous wall are altered by organization and ingrowth of smooth muscle cells and production of neointima. This process leaves damaged, incompetent, underlying valves, predisposing them to venous reflux. The mural inflammatory reaction breaks down collagen and elastin, leaving a noncompliant venous wall.[30, 31, 32, 33, 34, 35]

Persistent obstructive thrombus, coupled with valvular damage, ensures continuation of this cycle. Over time, the venous damage may become irreversible. Hemodynamic venous insufficiency is the underlying pathology of postthrombotic syndrome (PTS), also referred to as postphlebitic syndrome. If numerous valves are affected, flow does not occur centrally unless the leg is elevated. Inadequate expulsion of venous blood results in stasis and a persistently elevated venous pressure or venous hypertension. As fibrin extravasates and inflammation occurs, the superficial tissues become edematous and hyperpigmented. With progression, fibrosis compromises tissue oxygenation, and ulceration may result. After venous insufficiency occurs, no treatment is ideal; elevation and use of compression stockings may compensate, or surgical thrombectomy or venous bypass may be attempted.[37, 38, 39, 40]

With anticoagulation alone, as many as 75% of patients with symptomatic DVT present with PTS at 5-10 years.[40, 41] However, the incidence of venous ulceration is far less, at 5%. Of the half million patients with venous ulcers in the United States, 17-45% report having a history of DVT.[42]

Lower-extremity deep venous thrombosis

Most small thrombi in the lower extremities tend to resolve spontaneously after surgery. In about 15% of cases, however, these thrombi may extend into the proximal femoral venous system of the leg. Untreated proximal thrombi represent a significant source of clinically significant pulmonary emboli.

In the absence of rhythmic contraction of the leg muscles, as in walking or moving, blood flow in the veins slows and even stops in some areas, predisposing patients to thrombosis.[43]

In the postoperative patient, as many as one half of all isolated calf vein thrombi resolve spontaneously within a few hours, whereas approximately 15% extend to involve the femoral vein. A many as one third of untreated symptomatic calf vein DVT extend to the proximal veins.[44] At 1-month follow-up of untreated proximal DVT, 20% regress and 25% propagate. Although calf vein thrombi are rare sources of clinically significant pulmonary embolism (PE), the incidence of PE with untreated proximal thrombi is 29-50%.[44, 45] Most PEs are first diagnosed at autopsy.[46, 47]

Upper-extremity deep venous thrombosis

The 2 forms of upper-extremity DVT are (1) effort-induced thrombosis (Paget-von Schrötter syndrome) and (2) secondary thrombosis.

Effort induced thrombosis, or Paget-von Schrötter syndrome, accounts for 25% of cases.[48] Paget in England and von Schrötter in Germany independently described effort thrombosis more than 100 years ago. In this primary form of the disease, an underlying chronic venous compressive abnormality caused by the musculoskeletal structures in the costoclavicular space is present at the thoracic inlet and/or outlet. See the images below.



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Deep venous thrombosis (DVT). This contrast-enhanced study was obtained through a Mediport placed through the chest wall through the internal jugular ....



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Deep venous thrombosis (DVT). Superior vena cava syndrome is noted in a patient with lung cancer. The computed tomography scan demonstrates a hypoatte....

In 75% of patients with secondary thrombosis, hypercoagulability and/or indwelling central venous catheters are important contributing factors. In fact, with the advent of central venous catheters, upper-extremity and brachiocephalic venous thrombosis has become a more common problem.[49, 50, 51, 52]

For more information on upper-extremity DVT, see Imaging in Deep Venous Thrombosis of the Upper Extremity.

Pulmonary embolism

PE develops as venous thrombi break off from their location of origin and travel through the right heart and into the pulmonary artery, causing a ventilation perfusion defect and cardiac strain. PE occurs in approximately 10% of patients with acute DVT and can cause up to 10% of in hospital deaths.[53, 54] However, most patients (up to 75%) are asymptomatic. Traditionally, proximal venous thrombosis are thought to be at highest risk for causing pulmonary emboli; however, 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.[55]

Superior vena cava syndrome

Superior vena cava syndrome is caused by gradual compression of the superior vena cava (SVC).  Patients can present with dyspnea, cough, dysphagia, and swelling of the neck and upper extremities. SVC syndrome is most commonly caused by extrinsic compression from a malignant process, such as lung or breast cancer. However, thrombotic causes of SVC syndrome are increasing due to the more widespread use of central venous catheters and pacemakers. SVC syndrome is a clinical diagnosis, but it can be confirmed with plain radiography, computed tomography (CT) scanning, and venography.[56]

For cancer-related SVC syndrome, the treatment consists of chemotherapy and radiation directed at the obstructing tumor. For thrombotic causes, thrombolysis and anticoagulation may be used.[57] Increasingly, endovascular treatment with balloon dilation and stenting are being used with rapid resolution of symptoms.[58, 59]

For more information, see Superior Vena Cava Syndrome.

Etiology

Numerous factors, often in combination, contribute to deep venous thrombosis (DVT). These may be categorized as acquired (eg, medication, illness) or congenital (eg, anatomic variant, enzyme deficiency, mutation). A useful categorization may be an acute provoking condition versus a chronic condition, as this distinction affects the length of anticoagulant therapy.

The frequent causes of DVT are due to augmentation of venous stasis due to immobilization or central venous obstruction. Immobility can be as transient as that occurring during a transcontinental airplane flight or that during an operation under general anesthesia. Thus, risk factors include obesity, medications, pregnancy, trauma, malignancy, and genetic conditions.[60] It can also be extended, as during hospitalization for pelvic, hip, or spinal surgery, or due to stroke or paraplegia. Individuals in these circumstances warrant surveillance, prophylaxis, and treatment if they develop DVT.[61, 62]

Reduced blood flow from increased blood viscosity or central venous pressure

Increased blood viscosity may decrease venous blood flow. This change may be due to an increase in the cellular component of the blood in polycythemia rubra vera or thrombocytosis or a decrease in the fluid component due to dehydration.

Increased central venous pressure, either mechanical or functional, may reduce the flow in the veins of the leg. Mass effect on the iliac veins or inferior vena cava from neoplasm, pregnancy, stenosis, or congenital anomaly increases outflow resistance.

Anatomic variants contributing to venous stasis

Anatomic variants that result in diminution or absence of the inferior vena cava or iliac veins may contribute to venous stasis. In iliocaval thromboses, an underlying anatomic contributor is identified in 60-80% of patients. The best-known anomaly is compression of left common iliac vein at the anatomic crossing of the right common iliac artery. The vein normally passes under the right common iliac artery during its normal course.

In some individuals, this anatomy results in compression of the left iliac vein and can lead to band or web formation, subsequent stasis, and left leg DVT. The reasons are poorly understood. Compression of the iliac vein is also called May-Thurner syndrome or Cockett syndrome.

Inferior vena cava variants are uncommon. Anomalous development is most commonly detected and diagnosed on cross-sectional imaging or venography. The embryologic evolution of the inferior vena cava is from an enlargement or atrophy of paired supracardinal and subcardinal veins. Anomalous embryologic development may result in absence of the normal cava. These variations may increase the risk of symptoms because small-caliber vessels may be most subject to obstruction. In patients younger than 50 years who have deep venous thrombosis, the incidence of a caval anomaly is as high as 5%.[63]

A double or duplicated inferior vena cava results from lack of atrophy in part of the left supracardinal vein, resulting in a duplicate structure to the left of the aorta. The common form is a partial paired inferior vena cava that connects the left common iliac and left renal veins. When caval interruption, such as placement of a filter, is planned, these alternate pathways must be considered. As an alternative, the inferior vena cava may not develop. The most common alternate route for blood flow is through the azygous vein, which enlarges to compensate. If a venous stenosis is present at the communication of iliac veins and azygous vein, back pressure can result in insufficiency, stasis, or thrombosis.[64]

In rare cases, neither the inferior vena cava nor the azygous vein develops, and the iliac veins drain through internal iliac collaterals to the hemorrhoidal veins and superior mesenteric vein to the portal system of the liver. Hepatic venous drainage to the atrium is patent. Because this pathway involves small hemorrhoidal vessels, thrombosis of these veins can cause severe acute swelling of the legs.

Thrombosis of the inferior vena cava is a rare occurrence and is an unusual result of leg deep venous thrombosis unless an inferior vena cava filter is present and stops a large embolus in the cava, resulting in obstruction and extension of thrombosis. Common causes of caval thrombosis include tumors involving the kidney or liver, tumors invading the inferior vena cava, compression of the inferior vena cava by extrinsic mass, and retroperitoneal fibrosis.[65, 66]

Mechanical injury to vein

Mechanical injury to the vein wall appears to provide an added stimulus for venous thrombosis. Hip arthroplasty patients with the associated femoral vein manipulation represent a high-risk group that cannot be explained by just immobilization, with 57% of thrombi originating in the affected femoral vein rather than the usual site of stasis in the calf.[67] Endothelial injury can convert the normally antithrombogenic endothelium to become prothrombotic by stimulating the production of tissue factor, von Willebrand factor, and fibronectin.

Injury may be obvious, such as those due to trauma, surgical intervention, or iatrogenic injury, but they may also be obscure, such as those due to remote deep venous thrombosis (perhaps asymptomatic) or minor (forgotten) trauma. Previous DVT is a major risk factor for further DVT. The increased incidence of DVT in the setting of acute urinary tract or respiratory infection may be due to an inflammation-induced alteration in endothelial function.

According to the results of a meta-analysis of 64 studies encompassing 29,503 patients, peripherally inserted central catheters (PICCs) may double the risk for DVT in comparison with central venous catheters (CVCs).[68, 69] This was the largest review of the incidence, patterns, and risk for venous thromboembolism (VTE) associated with PICCs yet published; however, the findings were limited by the absence of any published randomized trials.

Compared with CVCs, PICCs were associated with an increased risk of DVT (odds ratio [OR], 2.55; but not of pulmonary embolism (no events).[69] The frequency of PICC-related DVT was highest in patients who were critically ill (13.91%) and patients who had cancer (6.67%).

Common risk factors for deep venous thrombosis

The presence of risk factors plays a prominent role in the assessing the pretest probability of DVT. Furthermore, transient risk factors permit successful short-term anticoagulation, whereas idiopathic deep venous thrombosis or chronic or persistent risk factors warrant long-term therapy.

In the MEDENOX study that evaluated 1102 acutely ill, immobilized admitted general medical patients, multiple logistic regression analysis found the following factors to be significantly and independently associated with an increased risk for VTE, most of which were asymptomatic and diagnosed by venography of both lower extremities[70] :

The most common risk factors are obesity, previous VTE, malignancy, surgery, and immobility. Each is found in 20-30% of patients. Hospitalized and nursing home patients often have several risk factors and account for one half of all DVT (with an incidence of 1 case per 100 population).[46, 71]  Obesity also appears to increases the risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage.[72]

The single most powerful risk marker remains a prior history of DVT, with as many as 25% of acute venous thrombosis occurring in such patients.[73] Pathologically, remnants of previous thrombi are often seen within the specimens of new acute thrombi. However, recurrent thrombosis may actually be the result of primary hypercoagulable states. Abnormalities within the coagulation cascade are the direct result of discrete genetic mutations within the coagulation cascade. Deficiencies of protein C, protein S, or antithrombin III account for approximately 5-10% of all cases of DVT.[74]

Age has been well studied as an independent risk factor for venous thrombosis development. Although a 30-fold increase in incidence is noted from age 30 to age 80, the effect appears to be multifactorial, with more thrombogenic risk factors occurring in the elderly than in those younger than 40 years.[73, 75] Venous stasis, as seen in immobilized patients and paralyzed limbs, also contributes to the development of venous thrombosis. Autopsy studies parallel the duration of bed rest to the incidence of venous thrombosis, with 15% of patients in those studies dying within 7 days of bedrest to greater than 80% in those dying after 12 weeks.[20] Within stroke patients, DVT is found in 53% of paralyzed limbs, compared with only 7% on the nonaffected side.[76]

Malignancy is noted in as many as 30% of patients with venous thrombosis.[73, 77] The thrombogenic mechanisms involve abnormal coagulation, as evidenced by 90% of cancer patients having some abnormal coagulation factors.[78] Chemotherapy may increase the risk of venous thrombosis by affecting the vascular endothelium, coagulation cascades, and tumor cell lysis. The incidence has been shown to increase in those patients undergoing longer courses of therapy for breast cancer, from 4.9% for 12 weeks of treatment to 8.8% for 36 weeks.[79] Additionally, DVT complicates 29% of surgical procedures done for malignancy.[80]

Postoperative venous thrombosis varies depending on a multitude of patient factors, including the type of surgery undertaken. Without prophylaxis, general surgery operations typically have an incidence of DVT around 20%, whereas orthopedic hip surgery can occur in up to 50% of patients.[81] The nature of orthopedic illnesses and diseases, trauma, and surgical repair or replacement of hip and knee joints predisposes patients to the occurrence of VTE disease. These complications are predictable and are the result of alterations of the natural equilibrium mechanisms in various disease states.[82] For more information, see Deep Venous Thrombosis Prophylaxis.

Based on radioactive labeled fibrinogen, about half of lower extremity thrombi develop intraoperatively.[83] Perioperative immobilization, coagulation abnormalities, and venous injury all contribute to the development of surgical venous thrombosis.

Genetic factors

Genetic mutations within the blood’s coagulation cascade represent those at highest risk for the development of venous thrombosis. Genetic thrombophilia is identified in 30% of patients with idiopathic venous thrombosis. Primary deficiencies of coagulation inhibitors antithrombin, protein C, and protein S are associated with 5-10% of all thrombotic events.[84, 85, 86] Altered procoagulant enzyme proteins include factor V, factor VIII, factor IX, factor XI, and prothrombin. Resistance of procoagulant factors to an intact anticoagulation system has also recently been described with the recognition of factor V Leiden mutation, representing 10-65% of patients with DVT.[87] In the setting of venous stasis, these factors are allowed to accumulate in thrombosis prone sites, where mechanical vessel injury has occurred, stimulating the endothelium to become prothrombotic.[88]

Factor V Leiden is a mutation that results in a form of factor Va that resists degradation by activated protein C, leading to a hypercoagulable state. Its importance lies in the 5% prevalence in the American population and its association with a 3-fold to 6-fold increased risk for VTE. Antiphospholipid syndrome is considered a disorder of the immune system, where antiphospholipid antibodies (cardiolipin or lupus anticoagulant antibodies) are associated with a syndrome of hypercoagulability. Although not a normal blood component, the antiphospholipid antibody may be asymptomatic. It is present in 2% of the population, and it may be detected in association with infections or the administration of certain drugs, including antibiotics, cocaine, hydralazine, procainamide, and quinine.[85]

Tests for these genetic defects are often not performed in patients with recurrent venous thrombosis because therapy remains symptomatic. In most patients with these genetic defects, lifetime anticoagulation therapy with warfarin or low molecular weight heparin (LMWH) is recommended after recurrent DVT without an alternative identifiable etiology documented. The risk of recurrent DVT is multiplied 1.4-2 times, with the most common genetic polymorphisms predisposing individuals to DVT. However, the low incidence of factor V Leiden and prothrombin G20210A may not warrant aggressive prophylaxis. Therefore, genetic testing might not be warranted until a second event occurs.[89]

Other conditions that can induce hypercoagulability

Other diseases and states can induce hypercoagulability in patients without other underlying risks for DVT. They can predispose patients to DVT, though their ability to cause DVT without intrinsic hypercoagulability is in question. The conditions include malignancy, dehydration, and use of medications (eg, estrogens). Acute hypercoagulable states also occur, as in disseminated intravascular coagulopathy (DIC) resulting from infection or heparin-induced thrombocytopenia.[90]

Summary of risk factors

A summary of risk factors is as follows:

Epidemiology

Deep venous thrombosis (DVT) and thromboembolism remain a common cause of morbidity and mortality in bedridden or hospitalized patients, as well as generally healthy individuals. The exact incidence of DVT is unknown because most studies are limited by the inherent inaccuracy of clinical diagnosis. Existing data that probably underestimate the true incidence of DVT suggest that about 80 cases per 100,000 population occur annually. Approximately 1 person in 20 develops a DVT in the course of his or her lifetime. About 600,000 hospitalizations per year occur for DVT in the United States.

In elderly persons, the incidence is increased four-fold. The in-hospital case-fatality rate for venous thromboembolism (VTE) is 12%, rising to 21% in elderly persons. In hospitalized patients, the incidence of venous thrombosis is considerably higher and varies from 20-70%. Venous ulceration and venous insufficiency of the lower leg, which are long-term complications of DVT, affect 0.5% of the entire population. Extrapolation of these data reveals that as many as 5 million people have venous stasis and varying degrees of venous insufficiency.

Age distribution for deep venous thrombosis

Deep venous thrombosis usually affects individuals older than 40 years. The incidence of VTE increases with age in both sexes. The age-standardized incidence of first-time VTE is 1.92 per 1000 person-years.

Prevalence of deep venous thrombosis by sex

The male-to-female ratio is 1.2:1, indicating that males have a higher risk of DVT than females.

Prevalence of deep venous thrombosis by race

From a demographic viewpoint, Asian and Hispanic populations have a lower risk of VTE, whereas whites and blacks have a higher risk (2.5-4 times higher).

Prognosis

Most cases of deep venous thrombosis (DVT) is occult and usually resolves spontaneously without complication. The principal long-term morbidity from DVT is postthrombotic syndrome (PTS), which complicates about a quarter of cases of symptomatic proximal DVT; most cases develop within 2 years afterward.

Death from DVT is attributed to massive pulmonary embolism (PE), which causes as many as 300,000 deaths annually in the United States.[1]  PE is the leading cause of preventable in-hospital mortality. The Longitudinal Investigation of Thromboembolism Etiology (LITE) that combined data from two prospective cohort studies, the Atherosclerosis Risk in Communities (ARIC) and the Cardiovascular Health Study (CHS) determined the incidence of symptomatic DVT and pulmonary embolism in 21,680 participants aged 45 years or older who were followed for 7.6 years.[91]

Thromboembolism and recurrent thromboembolism appear to be serious complications of inflammatory bowel disease.[92] In a study comprising 84 patients with inflammatory disease and a history of thromboembolism, of whom, 30% had recurrent thromboembolism, 70 patients (83%) developed venous thromboembolism (40% of which manifested as DVT and 23% as PE).[92]

History

Deep venous thrombosis (DVT) classically produces pain and limb edema; however, in a given patient, 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. Edema is the most specific symptom of DVT. Thrombus that involves the iliac bifurcation, the pelvic veins, or the vena cava produces leg edema that is usually 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. Massive edema with cyanosis and ischemia (phlegmasia cerulea dolens) is rare.

Leg pain occurs in 50% of patients, but this is entirely nonspecific. Pain can occur on dorsiflexion of the foot (Homans sign). Tenderness occurs in 75% of patients but is also found in 50% of patients without objectively confirmed DVT. When tenderness is present, it is usually confined to the calf muscles or along the course of the deep veins in the medial thigh. Pain and/or tenderness away from these areas is not consistent with venous thrombosis and usually indicates another diagnosis. The pain and tenderness associated with DVT does not usually correlate with the size, location, or extent of the thrombus. Warmth or erythema of skin can be present over the area of thrombosis.

Clinical signs and symptoms of pulmonary embolism as the primary manifestation occur in 10% of patients with confirmed DVT.

Even with patients with classic symptoms, as many as 46% have negative venograms.[2] Furthermore, as many as 50% of those with image-documented venous thrombosis lack specific symptoms.[3, 93] 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. (See Workup)

Physical Examination

No single physical finding or combination of symptoms and signs is sufficiently accurate to establish the diagnosis of deep venous thrombosis (DVT).

The classic finding of calf pain on dorsiflexion of the foot with the knee straight (Homans sign) has been a time-honored sign of DVT.[94] However, Homans sign is neither sensitive nor specific: it is present in less than one third of patients with confirmed DVT, and is found in more than 50% of patients without DVT.

Superficial thrombophlebitis is characterized by the finding of a palpable, indurated, cordlike, tender, subcutaneous venous segment. Forty percent of patients with superficial thrombophlebitis without coexisting varicose veins and with no other obvious etiology (eg, intravenous catheters, intravenous drug abuse, soft tissue injury) have an associated DVT. Patients with superficial thrombophlebitis extending to the saphenofemoral junction are also at higher risk for associated DVT.

If a patient is thought to have pulmonary embolism (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 PE 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.

Patients with venous thrombosis may have variable discoloration of the lower extremity. The most common abnormal hue is reddish purple from venous engorgement and obstruction. In rare cases, the leg is cyanotic from massive ileofemoral venous obstruction. This ischemic form of venous occlusion was originally described as phlegmasia cerulea dolens (“painful blue inflammation”). The leg is usually markedly edematous, painful, and cyanotic. Petechiae are often present.

In relatively rare instances, acute extensive (lower leg–to-iliac) occlusion of venous outflow may create a blanched appearance of the leg because of edema. The clinical triad of pain, edema, and blanched appearance is termed phlegmasia alba dolens (“painful white inflammation”), a term originally used to describe massive ileofemoral venous thrombosis and associated arterial spasm. This is also known as milk-leg syndrome when it is associated with compression of the iliac vein by the gravid uterus. The affected extremity is often pale with poor or even absent distal pulses. The physical findings may suggest acute arterial occlusion, but the presence of swelling, petechiae, and distended superficial veins point to this condition. As many as half the patients with phlegmasia alba dolens have capillary involvement, which poses a risk of irreversible venous gangrene with massive fluid sequestration. In severely affectedpatients, immediate therapyisnecessarytoprevent limb loss.

Pulmonary Embolism

As many as 40% of patients have silent pulmonary embolism (PE) when symptomatic deep venous thrombosis (DVT) is diagnosed.[4] Approximately 4% of individuals treated for DVT develop symptomatic PE. Almost 1% of postoperative hospitalized patients develop PE. The 10-12% mortality rate for PE in hospitalized patients underscores the need for prevention of this complication. Treatment options include anticoagulation therapy and placement of an inferior vena cava filter. If evidence of right heart failure is present or if adequate oxygenation cannot be maintained, the thrombus may be removed with pharmacomechanical thrombolytic intervention.

Electrocardiography may demonstrate ST-segment changes in patients with PE. The arterial oxygen saturation (PaO2) level may be lowered. All or none of these findings may be present, and the embolization may remain subclinical or silent. (See the images below.)



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Deep venous thrombosis (DVT). Lung scans are shown. LPO = left posterior oblique.



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Deep venous thrombosis (DVT). Spiral computed tomography scan showing a pulmonary thrombus.



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Deep venous thrombosis (DVT). This is the appearance of a normal pulmonary angiogram.



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Deep venous thrombosis (DVT). This is a positive pulmonary angiogram.

PE is most often diagnosed by means of ventilation/perfusion lung scanning, which is reported as having a low, moderate, or high probability of depicting PE. When the results of these studies are equivocal, the use of spiral CT scans may be able to demonstrate intravascular thrombosis. In many institutions, the criterion standard for diagnosing PE is pulmonary angiography.

Paradoxic Emboli

Although rare, paradoxic emboli can occur in patients with cardiac defects (usually atrial septal defect), who are at risk for the passage of emboli to the arterial circulation and resultant stroke or embolization of a peripheral artery. Patients can present after cardiac failure occurs late in life, with resultant bedrest that increases the risk for deep venous thrombosis.

Recurrent Deep Venous Thrombosis

Without treatment, one half of patients with deep venous thrombosis (DVT) have a recurrent, symptomatic venous thromboembolism (VTE) event within 3 months. After anticoagulation for an unprovoked VTE event is discontinued, the incidence is 5-15% per year. Presentations are similar, with pain and edema. However, the diagnosis may be difficult (ie, differentiating acute from chronic thrombus). Recurrence increases the risk of postthrombotic syndrome (PTS).

A review by Martinelli et al indicates that hormonal therapy, including estrogen-containing agents, does not appear to be associated with recurrent VTE in women younger than 60 years receiving anticoagulation with rivaroxaban or enoxaparin/vitamin K antagonists for confirmed VTE.[95] However, it was noted that abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/vitamin K antagonists.

Postthrombotic Syndrome

Postthrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT) that manifests months to many years after the initial event. Symptoms range from mild erythema and localized induration to massive extremity swelling and ulceration, usually exacerbated by standing and relieved by elevation of the extremity. Evaluations of the incidence or of improvements with therapy have been problematic because reporting is not standardized. Furthermore, correlation between objectively measured hemodynamic changes and the severity of PTS is poor.[96]

After symptomatic DVT is treated with anticoagulation, the incidence of PTS at 2 years is 25-50% despite long-term anticoagulation for iliofemoral DVT, and after 7-10 years, the incidence is 70-90%.[97, 98] The only current treatment is use of a compression hose and elevation. In many patients, this is only partly effective in relieving swelling, pain, and venous ulcers. In the United States, the annual direct cost of post–DVT, PTS-related venous ulcers is estimated to be $45 million per year, and 300,000 work days are lost.[99]

Approach Considerations

Routine blood tests that have the potential to help clinicians stratify patients with the risk for deep venous thrombosis (DVT) include D-dimer assay; levels of antithrombin III (ATIII), N-terminal pro-brain natriuretic peptide (NT-proBNP), and C-reactive protein (CRP); and erythrocyte sedimentation rate (ESR).[100]

A clinical practice guideline from the American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP) provides four recommendations for the workup of patients with probable DVT).[5] First, validated clinical prediction rules should be used to estimate the pretest probability of venous thromboembolism (VTE) and interpret test results. The Wells prediction rules for DVT and for pulmonary embolism meet this standard, although the rule performs better in younger patients without comorbidities or a history of VTE than it does in other patients.

Second, in appropriately selected patients with low pretest probability of DVT or pulmonary embolism, it is reasonable to obtain a high-sensitivity D-dimer. A negative result indicates a low likelihood of VTE. Third, in patients with intermediate to high pretest probability of lower-extremity DVT, ultrasonography is recommended.

Fourth, patients with intermediate or high pretest probability of pulmonary embolism require diagnostic imaging studies. Options include a ventilation-perfusion (V/Q) scan, multidetector helical computed axial tomography (CT), and pulmonary angiography; however, CT alone may not be sufficiently sensitive to exclude pulmonary embolism in patients who have a high pretest probability of pulmonary embolism.

VTE remains an underdiagnosed disease, and most cases of pulmonary embolism (PE) are diagnosed at autopsy. Diagnosis depends on a high level of clinical suspicion and the presence of risk factors that prompt diagnostic study. Because the presentation is nonspecific and because the consequence of missing the diagnosis is serious, it must be excluded whenever it is a feasible differential diagnosis. Because the prevalence of the disease is 15-30% in the population at clinical risk, a widely applicable (inexpensive and simple) screening test is required.

Conclusive diagnosis historically required invasive and expensive venography, which is still considered the criterion standard. Since 1990, the diagnosis has been obtained noninvasively by means of (still expensive) sonographic examination. The validation of the simpler and cheaper D-dimer test as an initial screening test permits a rapid, widely applicable screening that may reduce the rate of missed diagnoses. Algorithms are based on pretest probabilities and D-dimer results. As many of 40% of patients with a low clinical suspicion and a negative D-dimer result require no further evaluation.[101, 102]

Kleinjan et al have proposed a diagnostic algorithm that uses a combination of a clinical decision probability, D-dimer testing, and ultrasonographic findings to exclude upper extremity DVT (UEDVT).[103]  The algorithm was feasible and completed in 390 of 406 patients (96%), excluded UEDVT from 87 patients (21%) with an unlikely clinical score and normal D-dimer levels, and identified superficial venous thrombosis in 54 (13%) and UEDVT in 103 (25%) patients.[103]

Laboratory analysis has also been used in aiding the diagnosis of venous thrombosis. Protein S, protein C, ATIII, factor V Leiden, prothrombin 20210A mutation, antiphospholipid antibodies, and homocysteine levels can be measured. Deficiencies of these factors or the presence of these abnormalities all produce a hypercoagulable state. These are rare causes of DVT. Laboratory investigations for these abnormalities are primarily indicated when DVT is diagnosed in patients younger than 50 years, when there is a confirmed family history of a hypercoagulable state or a familial deficiency, when venous thrombosis is detected in unusual sites, and in the clinical setting of warfarin-induced skin necrosis.

D-Dimer Testing

D-dimers are degradation products of cross-linked fibrin by plasmin that are detected by diagnostic assays. D-dimer level may be elevated in any medical condition where clots form. D-dimer level is elevated in trauma, recent surgery, hemorrhage, cancer, and sepsis.[104] Many of these conditions are associated with higher risk for deep venous thrombosis (DVT).

D-dimer levels remain elevated in DVT for about 7 days. Patients presenting late in the course, after clot organization and adherence have occurred, may have low levels of D-dimer. Similarly, patients with isolated calf vein DVT may have a small clot burden and low levels of D-dimer that are below the analytic cutoff value of the assay. This accounts for the reduced sensitivity of the D-dimer assay in the setting of confirmed DVT.

Current evidence strongly supports the use of a D-dimer assay in the setting of suspected DVT. Most studies have confirmed the clinical utility of D-dimer testing, and most clinical algorithms incorporate its use. The D-dimer assay has a high sensitivity (up to 97%); however, it has a relatively poor specificity (as low as 35%)[105] and therefore should only be used to rule out DVT, not to confirm the diagnosis of DVT.

A negative D-dimer assay result rules out DVT in patients with low-to-moderate risk (Wells DVT score < 2). (See Risk Stratification.) A negative result also obviates surveillance and serial testing in patients with moderate-to-high risk and negative ultrasonographic findings. All patients with a positive D-dimer assay result and all patients with a moderate-to-high risk of DVT (Wells DVT score >2) require a diagnostic study (duplex ultrasonography).

Studies indicate that the D-dimer test can be used as a rapid screening measure in cases where leg swelling exists in the face of equivocal or negative clinical or radiologic findings. Forty percent of patients with a negative clinical examination and negative D-dimer test require no further clinical evaluation. Similarly, subjects with an elevated D-dimer test at 1 month following anticoagulant cessation have a significantly higher risk of recurrent venous thromboembolism (VTE).[106]

A randomized, multicenter, controlled trial involving 1723 patients found that selective testing of D-dimer levels lowered the proportion of patients who underwent ultrasonography and decreased the percentage of patients who needed D-dimer testing by 21.8%.[107, 108] This suggests that a selective D-dimer testing strategy based on clinical pretest probability (C-PTP), as opposed to testing all patients presenting with symptoms of a first DVT episode, can exclude DVT in more patients without increasing the rate of missed diagnoses.

Characteristics of different D-dimer assays

Many different D-dimer assays are available, with varying sensitivities and specificities. These assays are not standardized. They incorporate different monoclonal antibodies to the D-dimer fragment. Results may be reported quantitatively or qualitatively. Different units may be used; some assay results are reported as fibrinogen equivalent units (FEU) and others in nanograms per milliliter (ng/mL). The results of one assay cannot be extrapolated to another. Accordingly, physicians should know their hospital’s D-dimer assay.

All D-dimer assays have been evaluated in various validation studies that determine the assay’s sensitivity, specificity, and negative predictive value (NPV). Unfortunately, fewer management studies have been conducted to determine the safety of withholding anticoagulant therapy on the basis of a negative test result. Furthermore, the NPV of a specific assay falls as the pretest probability of the study population at risk for DVT increases. An assay with a sensitivity of 80% has an NPV of 97.6% in a low-risk patient. However, the NPV of the same assay is only 33% in high-risk patients with a pretest probability of 90% for DVT.

Traditional enzyme-linked immunosorbent assays (ELISAs), although accurate, are time-consuming and not practical for use in the emergency department. A rapid ELISA assay (VIDAS) with high sensitivity was validated in a large European trial. In that study a negative VIDAS D-dimer assay essentially ruled out DVT. All patients with a negative D-dimer result did not require further diagnostic testing with ultrasonography.[109]

The older qualitative latex agglutination assay is not accurate and should not be used for making treatment decisions in patients with suspected DVT. Newer latex-enhanced immunoturbidimetric and immunofiltration assays have high sensitivity and are available.

A rapid qualitative red blood cell agglutination assay (SimpliRED) is available. It is sensitive for proximal vein DVT but less so for calf vein DVT. A large study confirmed that, in low-risk patients with low pretest probability for DVT, a negative SimpliRED D-dimer result rules out DVT. Ultrasonography was not required in these patients.[110]

Coagulation Profile

Additional blood work should include coagulation studies to evaluate for a hypercoagulable state, if clinically indicated. A prolonged prothrombin time or activated partial thromboplastin time does not imply a lower risk of new thrombosis. Progression of deep venous thrombosis and pulmonary embolism can occur despite full therapeutic anticoagulation in 13% of patients.

Imaging in Deep Venous Thrombosis

Imaging studies used in deep venous thrombosis (DVT) include ultrasonography, venography, impedance plethysmography, magnetic resonance imaging (MRI), and nuclear imaging. Ultrasonography is the current first-line imaging examination for DVT because of its relative ease of use, absence of irradiation or contrast material, and high sensitivity and specificity in institutions with experienced sonographers.

The criterion standard to diagnostic imaging for DVT remains venography with pedal vein cannulation, intravenous contrast injection, and serial limb radiographs. However, the invasive nature and significant consumption of resources are only 2 of its many limitations.

In some countries, impedance plethysmography (IPG) has been the initial noninvasive diagnostic test of choice and has been shown to be sensitive and specific for proximal vein thrombosis. However, IPG also has several other limitations; among them are insensitivity for calf vein thrombosis, nonoccluding proximal vein thrombus, and iliofemoral vein thrombosis above the inguinal ligament.

MRI has increasingly been investigated for evaluation of suspected DVT. Limited studies suggest the accuracy approaches that of contrast venography. MRI is the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis when CT venography is contraindicated or technically inadequate. Radiolabeled peptides that bind to various components of a thrombus have been investigated. The cost of the tests and the inability to visualize the anatomy of the area of involvement (which many clinicians prefer) has lead to the underuse of scintigraphy.

For more information, see Imaging in Deep Venous Thrombosis.

Additionally, note that imaging modalities, techniques, and findings may be specific to the upper extremities and lower extremities.

For more information, see Imaging in Deep Venous Thrombosis, Lower Extremity.

Risk Stratification

The Wells clinical prediction guide quantifies the pretest probability of deep venous thrombosis (DVT). The model enables physicians to reliably stratify their patients into high-risk, moderate-risk, or low-risk categories. Combining this with the results of objective testing greatly simplifies the clinical workup of patients with suspected DVT. The Wells clinical prediction guide incorporates risk factors, clinical signs, and the presence or absence of alternative diagnoses.

Predictors of venous thromboembolism (VTE) in a Japanese study comprising data from 3,578 patients diagnosed with VTE over 6 years (2008-2013) included the presence of malignancies and the use of antipsychotic agents and/or nonsteroidal anti-inflammatory agents.[111]

Please go to the main article on Deep Venous Thrombosis Risk Stratification to see complete information on this topic.

Approach Considerations

The primary objectives for the treatment of deep venous thrombosis (DVT) are to prevent pulmonary embolism (PE), reduce morbidity, and prevent or minimize the risk of developing the postthrombotic syndrome (PTS).

The mainstay of medical therapy has been anticoagulation since the introduction of heparin in the 1930s.[112] Other anticoagulation drugs have subsequently been added to the treatment armamentarium over the years, such as vitamin K antagonists and low-molecular-weight heparin (LMWH). More recently, mechanical thrombolysis has become increasingly used as endovascular therapies have increased. Absolute contraindications to anticoagulation treatment include intracranial bleeding, severe active bleeding, recent brain, eye, or spinal cord surgery, pregnancy, and malignant hypertension. Relative contraindications include recent major surgery, recent cerebrovascular accident, and severe thrombocytopenia.

The immediate symptoms of DVT often resolve with anticoagulation alone, and the rationale for intervention is often reduction of the 75% long-term risk of PTS. Systemic IV thrombolysis once improved the rate of thrombosed vein recanalization; however, it is no longer recommended because of an elevated incidence of bleeding complications, slightly increased risk of death, and insignificant improvement in PTS. The lack of a significantly reduced incidence of PTS after systemic thrombolysis (40-60%) likely reflects the inadequacy of the relatively low threshold volume of thrombus removal that was considered successful.

Thrombolytic therapy is recommended (systemic preferred over catheter directed) in hypotensive individuals with an acute PE.[113]  Those with high-risk PE presenting in shock should undergo systemic thrombolysis; when thrombolysis is contraindicated owing to a high risk of bleeding, consider surgical thrombectomy or catheter direct thrombolysis.[114]

The bleeding risk of systemic thrombolysis is similar to that of catheter-directed thrombolysis, and the risk of PTS may further decrease risk. However, whether catheter-directed thrombolysis is preferred to anticoagulation has not been examined. The addition of percutaneous mechanical thrombectomy to the interventional options may facilitate decision-making, because recanalization may be achieved faster than before and with a decreased dose of lytic; therefore, the bleeding risk may be decreased.

Inpatient Versus Outpatient Treatment

Acute DVT may be treated in an outpatient setting with LMWH. Patients with low-risk PE may be safely discharged early from hospital or receive only outpatient treatment with LMWH, followed by vitamin K antagonists, although nonvitamin K-dependent oral anticoagulants may be as effective but safer than the LMWH/vitamin K antagonist regimen.[115]

Anticoagulant therapy is recommended for 3-12 months depending on site of thrombosis and on the ongoing presence of risk factors. If DVT recurs, if a chronic hypercoagulability is identified, or if PE is life threatening, lifetime anticoagulation therapy may be recommended. This treatment protocol has a cumulative risk of bleeding complications of less than 12%.

Most patients with confirmed proximal vein DVT may be safely treated on an outpatient basis. Exclusion criteria for outpatient management are as follows:

Admitted patients may be treated with a LMWH, fondaparinux, or unfractionated heparin (UFH). Warfarin 5 mg PO daily is initiated and overlapped for about 5 days until the international normalized ratio (INR) is therapeutic >2 for at least 24 hours.

For admitted patients treated with UFH, the activated partial thromboplastin time (aPTT) or heparin activity level must be monitored every 6 hours while the patient is taking intravenous (IV) heparin until the dose is stabilized in the therapeutic range. Patients treated with LMWH or fondaparinux do not require monitoring of the aPTT.

Platelets should be monitored. Heparin or LMWH should be discontinued if the platelet count falls below 75,000. Fondaparinux is not associated with hepatin-induced thrombocytopenia (HIT).

Consultations

Consultations with the following specialists are indicated:

General Principles of Anticoagulation

Anticoagulant therapy remains the mainstay of medical therapy for deep venous thrombosis (DVT) because it is noninvasive, it treats most patients (approximately 90%) with no immediate demonstrable physical sequelae of DVT, it has a low risk of complications, and its outcome data demonstrate an improvement in morbidity and mortality. Long-term anticoagulation is necessary to prevent the high frequency of recurrent venous thrombosis or thromboembolic events. Anticoagulation does have problems. Although it inhibits propagation, it does not remove the thrombus, and a variable risk of clinically significant bleeding is observed.

First-line therapy for non-high risk venous thromboembolism (VTE) or pulmonary embolism (PE) consists of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, or edoxaban) over vitamin K antagonists (VKAs).[113, 114]  VKAs are also recommended over low-molecular-weight heparin (LMWH), unless VTE is associated with malignancy, in which case LMWH is preferred over VKAs or any direct oral anticoagulants.[113]  

When the risk of VTE recurrence is high in patients with subsegmental PE without DVT, the American College of Chest Physicians (ACCP) recommends anticoagulation over surveillance; when the VTE recurrence risk is low in these patients, surveillance over anticoagulation is suggested.[113]

Inferior vena cava filters are not recommended in patients with acute VTE on anticoagulant therapy.[113]

Barring contraindications to aspirin therapy, aspirin is recommended to prevent recurrent VTE in patients with an unprovoked proximal DVT or PE following anticoagulation cessation.[113]

Park and Byun indicate that possibilities for advances in anticoagulant delivery systems include expansion of new oral agents and their antidotes, reducing the size of heparins, developing oral or topical heparins, and modifying physical or chemical formulations.[116]  For example, Ita suggests that transdermal delivery may potentially bypass known issues with heparin use, such as short half-life and unpredictable bioavailability, and offer improved patient compliance, convenience, ease of dosing termination, as well as avoid the first-pass effect.[112]

For more information, see General Principles of Anticoagulation in Deep Venous Thrombosis.

Heparin Use in Deep Venous Thrombosis

Heparin products used in the treatment of deep venous thrombosis (DVT) include unfractionated heparin and low molecular weight heparin (LMWH) The efficacy and safety of low-molecular-weight heparin (LMWH) for the initial treatment of DVT have been well established in several trials. Traditionally, heparin has been used only for admitted patients with DVT. Regular unfractionated heparin was the standard of care until the introduction of LMWH products. Heparin prevents extension of the thrombus and has been shown to significantly reduce (but not eliminate) the incidence of fatal and nonfatal pulmonary embolism and recurrent thrombosis.

Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity. The larger fragments exert their anticoagulant effect by interacting with antithrombin III (ATIII) to inhibit thrombin. ATIII, the body’s primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process. The low-molecular-weight fragments exert their anticoagulant effect by inhibiting the activity of activated factor X. The hemorrhagic complications attributed to heparin are thought to arise from the larger higher-molecular-weight fragments. LMWH is prepared by selectively treating unfractionated heparin to isolate the low-molecular-weight (< 9000 Da) fragments.

Patients with recurrent venous thromboembolism (VTE) while on treatment with a non-LMWH anticoagulant should be switched to LMWH therapy.[113] Those who suffer recurrent VTE while on LMWH therapy should receive an increased dose of LMWH.[113]

For more information, see Heparin Use in Deep Venous Thrombosis.

Factor Xa and Direct Thrombin Inhibitors

Fondaparinux

Fondaparinux, a direct selective inhibitor of factor Xa, overcomes many of the aforementioned disadvantages of low-molecular-weight heparins (LMWHs). Pharmacokinetic studies of fondaparinux reveal that only a single-daily subcutaneous dose is required. Furthermore, a single dose of 7.5 mg is effective over a wide range of patient weights between 50 and 100 kg. Daily doses of 5 mg or 10 mg are appropriate for patients who weigh less or more than that weight range. Heparin-induced thrombocytopenia (HIT) has not been reported. Therapeutic monitoring of laboratory parameters such as the prothrombin time or activated partial thromboplastin time (aPTT) is also not required. In some regions, the cost of therapy with fondaparinux is less than enoxaparin when it is being used to bridge therapy to a vitamin K antagonist (VKA).

The combination of two factor Xa inhibitors may be an effective treatment strategy for acute venous thromboembolism (VTE).[117]  In an observational study, 80 of 87 consecutive Japanese patients with VTE who received SC fondaparinux for 7-10 days and then were switched to oral rivaroxaban for 7-14 days had treatment success. Both D-dimer levels and quantitative ultrasound thrombosis (QUT) scores were improved with the use of fondaparinux, and further reductions were achieved using rivaroxaban.[117]

Buller and his coauthors on behalf of the Matisse Investigators conducted a randomized, double-blind, international study of fondaparinux versus enoxaparin on 2,205 patients with objectively confirmed acute deep venous thrombosis (DVT) and found the two agents to be comparable in safety and efficacy.[6] Patients were randomly assigned to receive fondaparinux or enoxaparin therapy. Fondaparinux was administered as a single 7.5-mg subcutaneous daily dose, with adjustments made for those patients weighing less than 50 kg (5 mg) or greater than 100 kg (10 mg). Enoxaparin was given 1 mg/kg subcutaneously twice daily. Both agents were bridged with a VKA until a therapeutic international normalized ratio (INR) was achieved. Anticoagulation with a VKA was continued for 3 months. Efficacy was measured by the rate of recurrent VTE in the 3-month follow-up period after enrollment. Safety was assessed by the incidence of major bleeding and mortality over the same interval.[6]

The recurrence rate showed a nonsignificant trend in favor of fondaparinux (3.9%) compared with enoxaparin (4.1%) (absolute difference = 0.15%; 95% CI, 1.8% to -1.5%).[6] The conservative noninferiority margin was attained, and fondaparinux was determined to be equally as effective as enoxaparin for the treatment of DVT. Major bleeding rates were essentially identical, and mortality rates were also comparable. In a subgroup analysis, the authors also evaluated the relationship between the recurrence rate, the bleeding risks, and the patients’ body weight. In general, the safety and efficacy of fondaparinux were independent of body weight. However, patients with mild renal insufficiency and a low creatinine clearance had the same risk of bleeding in both the LMWH and fondaparinux groups. Overall, the authors concluded that once-daily fondaparinux was as effective and as safe as twice-daily, weight-adjusted enoxaparin.[6]

The Matisse DVT trial confirmed that fondaparinux and enoxaparin have similar safety and efficacy for the initial treatment of DVT. Only one fixed-dosage regimen for fondaparinux is required for patients who weigh between 50 kg and 100 kg, and only one subcutaneous dose per day is required. This greatly simplifies the treatment of DVT and facilitates outpatient therapy. In the original study, about one third of the patients were treated partially or entirely as outpatients without any increased risk when compared with those treated as inpatients.

In renal insufficiency with a creatinine clearance less than 30 mL/min, major bleeding occurred in 2 of 25 patients (8%) on fondaparinux versus 1 of 18 patients (5.6%) treated with enoxaparin (P = NS). Because of the small sample size and the higher risk of bleeding, fondaparinux is contraindicated in patients with renal insufficiency and a creatinine clearance less than 30 mL/min.

In the event of a major bleed, protamine sulfate partially reverses the anticoagulant effect of enoxaparin. However, no specific antidote to fondaparinux is available. A recent study revealed that a bolus dose of 90 mcg/kg of recombinant factor VIIa reversed the anticoagulant effect of fondaparinux, at least in healthy volunteers given a larger 10-mg dose.[118]

Rivaroxaban

Rivaroxaban (Xarelto) is an oral factor Xa inhibitor approved by the FDA in November 2012 for treatment of DVT or pulmonary embolism (PE) and for reduction of the risk of recurrent DVT and PE after initial treatment.[7, 8, 9]  Approval for this indication was based on studies totaling 9478 patients with DVT or PE. Participants were randomly assigned to receive rivaroxaban, a combination of enoxaparin and a VKA (eg, warfarin), or a placebo. Study endpoints were designed to measure the number of patients who experienced recurrent symptoms of DVT, PE, or death after receiving treatment.

Data from a pooled analysis of the EINSTEIN-DVT[7] and EINSTEIN-PE[8] trials suggested that rivaroxaban is as effective in preventing VTE recurrence as enoxaparin followed by a VKA and may be associated with less bleeding[9] ; in addition, the data suggested that there are no grounds for avoiding rivaroxaban use in high-risk groups (eg, fragile patients, cancer patients, and patients with a large clot).

Approximately 2.1% of patients treated with rivaroxaban experienced recurrent DVT or PE, compared with 1.8-3% treated with the enoxaparin and VKA combination.[7, 8]

Additionally, results from extended treatment demonstrated a reduced risk of recurrent DVT and PE. Approximately 1.3% in the rivaroxaban group experienced recurrent DVT or PE, compared with 7.1% in the placebo group.[119, 120]

Apixaban

In March 2014, the FDA approved apixaban (Eliquis) for the additional indication of prophylaxis of DVT and PE in adults who have undergone hip- or knee-replacement surgery. Support for this new indication was a result of the ADVANCE 1, 2, and 3 clinical trials that enrolled nearly 12,000 patients.[121, 122, 123] Apixaban was originally approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In August 2014, apixaban was approved for treatment of DVT and PE.[124] The approval for treatment of PE and prevention of recurrence was based on the outcome of the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) and AMPLIFY-EXT (extended treatment) studies, in which apixaban therapy was compared with enoxaparin and warfarin treatment. The AMPLIFY study showed that, in comparison with the standard anticoagulant regimen, apixaban therapy resulted in a 16% reduction in the risk of a composite endpoint that included recurrent symptomatic venous thromboembolism (VTE) or VTE-associated death.[125, 126]

Data from the AMPLIFY-EXT trial showed that extended anticoagulation (12 months) with apixaban shortened hospital stays, reduced symptomatic recurrent venous thromboembolism or all-cause death without an associated increase in major episodes of hemorrhage when compared with placebo.[127]

Dabigatran

Dabigatran (Pradaxa) inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. This agent was FDA approved in 2010 to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In April 2014, it was approved for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days. Additionally, it was approved to reduce the risk of DVT and PE recurrence in patients who have been previously treated. Approval was based on results from 4 global phase III trials that showed dabigatran was noninferior to warfarin and had a lower risk of major or clinically relevant bleeding compared with warfarin.[128, 129, 130] There have been reports of severe and fatal bleeding in users of the drug.

The RE-COVER and RE-COVER II trials included patients with DVT and PE who were treated with parenteral anticoagulant therapy for 5-10 days. Results showed dabigatran was noninferior to warfarin in reducing DVT and PE after a median of 174 days of treatment with a lower risk of bleeding compared with warfarin.[128, 129]

The RE-SONATE trial and RE-MEDY trials included patients (n=2856) with acute DVT and PE who had completed at least 3 months of anticoagulant therapy. Results from this trial showed dabigatran was noninferior to warfarin in the extended treatment of VTE and carried a lower risk of major or clinically relevant bleeding than warfarin.[130]

Edoxaban

Edoxaban (Savaysa) was approved by the FDA in January 2015 for the treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days.[131] Approval was based on the Hokusai-VTE study that included 4,921 patients with DVT and 3,319 patients with PE.[131, 132]

Among patients with PE, 938 had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels.[132] There was a 3.3% rate of recurrent VTE in this subgroup in those who received edoxaban compared to 6.2% in the group that received warfarin. The investigators concluded that edoxaban was not only noninferior to high-quality standard warfarin therapy but also caused significantly less bleeding in a broad spectrum of patients with VTE, including those with severe PE.[132]

Betrixaban

Betrixaban (Bevyxxa), a FXa inhibitor, was approved by the FDA in June 2017.[133] It is indicated for the prophylaxis of VTE in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE.[133]

Approval of betrixaban was based on data from the phase 3 APEX studies.[134, 135] These randomized, double-blind, multinational clinical trials compared extended-duration betrixaban (35-42 days) to short-duration enoxaparin (6-14 days) for VTE in 7,513 acutely medically ill hospitalized patients with VTE risk factors.[133, 134, 135] Patients in the betrixaban group received an initial dose of 160 mg orally on day 1, followed by 80 mg once daily for 35-42 days, and received a placebo injection once daily for 6-14 days. Patients in the enoxaparin group received 40 mg subcutaneously once daily for 6-14 days and took an oral placebo once daily for 35-42 days.[133, 134, 135]

Efficacy was measured in 7,441 patients using a composite outcome score composed of the occurrence of asymptomatic or symptomatic proximal DVT, nonfatal PE, stroke, or VTE-related death.[133, 134, 135]  Those who received betrixaban showed significant decreases in VTE events (4.4%) compared with patients in the enoxaparin group (6%).

Duration of Anticoagulation

For the first episode of deep venous thrombosis (DVT), patients should be treated for 3-6 months. Recurrent episodes should be treated for at least 1 year.

The American College of Chest Physicians (ACCP) recommends cessation of anticoagulant therapy after 3 months of treatment in those with (1) surgery-associated acute proximal DVT, (2) an acute proximal DVT or PE provoked by a nonsurgical transient risk factor, and (3) a first unprovoked VTE and a high risk of bleeding.[113] (In those with a low or moderate bleeding risk, extend anticoagulation without a scheduled stop date.)[113]

Prandoni et al found that the use of ultrasonography to determine the duration of anticoagulation can reduce recurrences of venous thromboembolism after a first episode of acute proximal DVT. In the study, 538 consecutive outpatients who had completed an uneventful 3-month period of anticoagulation were randomized to receive either fixed-duration anticoagulation (< 9 months for secondary DVT and up to 21 months for unprovoked thrombosis) or flexible-duration anticoagulation, with treatment discontinued once ultrasound showed recanalization of the affected veins. Recurrent venous thromboembolism developed in 17.2% of the patients allocated to fixed-duration anticoagulation and 11.9% of the patients allocated to flexible-duration anticoagulation; no significant difference was noted in the rate of major bleeding.[136]

Patients with cancer have a particularly higher rate of DVT recurrence than noncancer patients. Long-term therapy for DVT is strongly recommended. Studies have shown a lower rate of venous thromboembolism (VTE) recurrence without increasing the risk of bleeding with low-molecular-weight heparin (LMWH) therapy. Reports also describe that the LMWH compounds may decrease the all-cause mortality rate. The author recommends LMWH therapy alone without crossover to warfarin if the patient’s insurance covers it.

Indefinite therapy is recommended for patients with recurrent episodes of venous thrombosis regardless of the cause. The risk of recurrent thromboembolism during a 4-year follow-up period was reduced from 21% to 3% with continued anticoagulation. However, the incidence of major bleeding increased from 3% to 9%.[137]

Long-term therapy with LMWH has been shown to be as effective as warfarin in the treatment of venous thrombosis, except in those patients with a concurrent malignancy. In this subgroup, LMWH was shown to be more effective than oral therapy.[138, 139] Initial studies have also shown LMWH to be effective in pregnant patients, but long-term, large randomized trials have yet to be completed.[140]

Complications of Anticoagulant Therapy

Hemorrhagic complications are the most common adverse effects of anticoagulant therapy. Anticoagulation therapy for 3-6 months results in major bleeding complications in 3-10% of patients.[141] High-risk populations (>65 y with a history of stroke, gastrointestinal [GI] bleed, renal insufficiency, or diabetes) have a 5-23% risk of having major hemorrhage at 90 days. Patients who require yearlong or indefinite anticoagulation (because of chronic risk factors) have double the risk of hemorrhage. Significant bleeding (ie, hematemesis, hematuria, GI hemorrhage) should be thoroughly investigated because anticoagulant therapy may unmask a preexisting disease (eg, cancer, peptic ulcer disease, arteriovenous malformation).

The treatment of hemorrhage while taking heparin depends on the severity of the bleeding and the extent to which the activated partial thromboplastin time (aPTT) is elevated above the therapeutic range. Patients who hemorrhage while receiving heparin are best treated by discontinuing the drug. The half-life is relatively short, and the aPTT usually returns to the reference range within a few hours. Treatment with fresh frozen plasma or platelet infusions is ineffective. For severe hemorrhage, such as intracranial or massive gastrointestinal bleeding, heparin may be neutralized by protamine at a dose of 1 mg for every 100 units. Protamine should be administered at the same time that the infusion is stopped.

The treatment of major hemorrhage associated with low-molecular-weight heparin (LMWH) is similar to heparin. However, the half-life of these agents is longer (4-6 h). As with heparin, fresh frozen plasma or platelet transfusions are ineffective. Protamine may be used, but it only reverses 60% of the drug’s effects.

The risk of bleeding on warfarin is not linearly related to the elevation of the international normalized ratio (INR). The risk is conditioned by other factors, including poor follow-up, drug interactions, age, and preexisting disorders that predispose to bleeding.

Patients who hemorrhage while receiving oral warfarin are treated by withholding the drug and administering vitamin K. Severe life-threatening hemorrhage is managed with fresh frozen plasma in addition to vitamin K. Recombinant factor VIIa is another option especially for central nervous system hemorrhage.

Additional complications include the following:

Emerging Anticoagulant Agents

The qualities desired in the ideal anticoagulant are ease of administration, efficacy and safety (with minimal complications or adverse effects), rapid onset, a therapeutic half-life, and minimal or no monitoring. Predictable and reversible action, with few drug or dietary interactions, and cost also are important. Achieving all these criteria in a single agent has not yet been achieved. Each of the anticoagulant agents available today has generally been able to incorporate some, but not all, of these characteristics.

In patients with deep venous thrombosis (DVT), anticoagulation remains the cornerstone of treatment. The relatively recent development of novel oral anticoagulants has provided clinicians with an expanding set of options for DVT treatment.[142]

Current research in anticoagulants involves investigations into drugs that act on various phases of the coagulation cascade. Drugs under investigation that act in the initiation phase include tissue factor pathway inhibitors (TFPIs) and nematode anticoagulant peptide (NAPc2). Drugs that act on the third stage of the coagulation cascade, the thrombin activity phase, include the direct thrombin inhibitors. A partial listing of these emerging new anticoagulants includes razaxaban, idraparinux, bivalirudin, lepirudin, and ximelagatran.

For more information, see Emerging Anticoagulant Agents in Deep Venous Thrombosis.

Reversal of Anticoagulation

Anticoagulation-related major bleeding is associated with an increased risk of death and thrombotic events, independent of the class of anticoagulant used. Although older agents of anticoagulation and their reversal are well studied, the newer agents lack similar antidotes. With the increasing use of non–vitamin K antagonist oral anticoagulants (NOAC), the number of patients who require reversal of their anticoagulant effects can be expected to rise. The following section describes the reversal agents for both older and new anticoagulants.

Heparin

Heparin has a relatively short half-life of about 60–90 minutes and, therefore, the anticoagulant effect of therapeutic doses of heparin will mostly be eliminated at 3-4 hours after termination of continuous intravenous administration.

For a more immediate neutralization of heparin, protamine sulfate can be administered at a dose of 1 mg for every 100 units of heparin. Protamine was originally isolated from fish sperm and binds to heparin to form a stable, biologically inactive complex.[143, 144]

Lower molecular weight heparins

Currently, there are no specific antidotes to low molecular weight heparins. Recombinant FVIIa (rVIIA) has been shown to stop bleeding in patients anticoagulated with fondaparinux; however, no randomized controlled trials on such patients have been conducted.

Warfarin

Vitamin K

In patients with clinically significant bleeding, vitamin K can be used to reverse the anticoagulant effect of vitamin K antagonists (VKA). Vitamin K can be given orally or intravenously. The parenteral route has a more rapid onset; however, it is associated with a slightly increased risk of allergic reaction.

Fresh frozen plasma (FFP)

In case of a life-threatening emergency, FFP can be used for the reversal of VKA. FFP contains all the coagulation factors in normal concentrations. However, FFP should be used with caution, as it has the potential to cause volume overload, allergic reaction, and transfusion-related reactions (eg, transfusion-related acute lung injury).[145]

Prothrombin complex concentrates (PCCs)

In the case of serious and life-threatening bleeding, immediate correction of the international normalized ratio (INR) can be achieved by the administration of PCCs. These contain 3 or 4 of the vitamin K–dependent coagulation factors, as well as proteins C and S. In a prospective study, administration of PCCs has been shown to result in sustained hemostasis in patients using VKA.

Non–vitamin K antagonist oral anticoagulants (NOACs)

The new oral anticoagulant factor Xa or IIa inhibitors have numerous advantages over traditional VKAs, including rapid therapeutic effectiveness, ease of dosing, and lack of monitoring. Until recently, there were no approved drug-specific reversal agents for the NOACs.  A number of drugs are currently under development.[146, 147]

Due to the short half-life of FXa inhibitors, discontinuation of the drugs suffice in clinical situations in which there is time to await spontaneous clearance.

Currently, PCCs can be used to address severe bleeding in patients taking NOACs when administered in high enough dosages. Some guidelines suggest an initial dose of 25 to 50 U/kg of PCCs in life-threatening emergencies, to be repeated if necessary.

Idarucizumab (Praxbind)

Idarucizumab is a humanized antibody fragment directed against dabigatran. This agent has been shown to completely reverse the anticoagulant effect of dabigatran within minutes; on October 16, 2015, it was approved by the FDA as an antidote for dabigatran.[148, 149, 150, 151]

Andexanet alfa

Andexanet alfa is a recombinant, modified FXa molecule that acts as a decoy protein that is catalytically inactive but has a high affinity for FXa inhibitors. It is being developed as an antidote for apixaban, edoxaban, and rivaroxaban. Andexanet alfa has been shown to reverse the anticoagulant effects of apixaban and rivaroxaban in human volunteers, and more studies are ongoing.[152]

Aripazine (PER977, ciraparantag)

Aripazine is a synthetic small molecule that has broad activity against both old (heparin, low molecular weight heparin) and new oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban). A 2014 study of human volunteers demonstrated that administration of aripazine reversed the prolonged clotting time caused by edoxaban. Further human trials are ongoing.[153]

Pharmacologic Thrombolysis

Use of thrombolytic medications to lyse deep venous thrombosis can cause intracranial bleeding, though this is infrequent, and death or impairment can result. Accordingly, careful assessment of the indications for lysis against the possibility of bleeding must be carried out before pharmacologic thrombolysis is attempted.

The need should be compelling when thrombolysis is considered in a setting of known contraindications. Factors such as recent surgery, stroke, gastrointestinal or other bleeding, and underlying coagulopathy increase the bleeding risk when the thrombolytic medication is administered. The process of obtaining informed consent should include a discussion of these risks.

General Principles of Endovascular Intervention

Percutaneous transcatheter treatment of patients with deep venous thrombosis (DVT) consists of thrombus removal with catheter-directed thrombolysis, mechanical thrombectomy, angioplasty, and/or stenting of venous obstructions. Consensus has been reached regarding indications for the procedure, although it is based on midlevel evidence from nonrandomized controlled trials. The goals of endovascular therapy include reducing the severity and duration of lower-extremity symptoms, preventing pulmonary embolism, diminishing the risk of recurrent venous thrombosis, and preventing postthrombotic syndrome. A randomized controlled trial comparing catheter-directed thrombolysis to conventional anticoagulation demonstrated a lower incidence of postthrombotic syndrome and improved iliofemoral patency in patients with a high proximal DVT and low risk of bleeding.[154]

Indications for intervention include the relatively rare phlegmasia or symptomatic inferior vena cava thrombosis that responds poorly to anticoagulation alone, or symptomatic iliofemoral or femoropopliteal DVT in patients with a low risk of bleeding. Contraindications are the same as those for thrombolysis in general. Absolute contraindications include active internal bleeding or disseminated intravascular coagulation, a cerebrovascular event, trauma, or neurosurgery within 3 months. Unfortunately, most patients with DVT have absolute contraindications to thrombolytic therapy. The American College of Chest Physicians (ACCP) consensus guidelines recommend thrombolytic therapy only for patients with massive ileofemoral vein thrombosis associated with limb ischemia or vascular compromise.[113, 155]

For more information, see Inferior Vena Caval Thrombosis.

Percutaneous mechanical thrombectomy devices are a popular adjunct to catheter-directed thrombolysis. Although these devices may not completely remove thrombus, they are effective for debulking and for minimizing the dose and time required for infusing a thrombolytic. Percutaneous mechanical thrombectomy has developed as an attempt to shorten treatment time and avoid costly ICU stays during thrombolytic infusion. The most basic mechanical method for thrombectomy is thromboaspiration, or the aspiration of thrombus through a sheath. Mechanical disruption of venous thrombosis has the potential disadvantage of damaging venous endothelium and valves, in addition to thrombus fragmentation and possible pulmonary embolism.

For more information, see Percutaneous Transcatheter Treatment of Deep Venous Thrombosis.

Surgical Thrombectomy

Surgical thrombus removal has traditionally been used in patients with massive swelling and phlegmasia cerulea dolens. 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.

Precisely defining the location and extent of thrombosis before considering any surgical approach to the problem is important. Duplex ultrasonography 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.

The patient must be heparinized before the procedure. Traditional venous thrombectomy is performed by surgically exposing the common femoral vein and saphenofemoral junction through a longitudinal skin incision. A Fogarty catheter is passed through the clot, and the balloon is inflated and withdrawn, 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. Venography is mandatory to confirm the clearance of the thrombus. Back bleeding does not indicate clot clearance because a patent valve can block flow, or flow can be present with patent tributaries.

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. 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 and promoting collateral development. The fistula is usually performed between the saphenous vein and the femoral vein. 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.

Outcomes from multiple studies have shown rethrombosis rates around 12% when a temporary arteriovenous fistula is used. Optimal results were found in thrombosis less than 7 days, clearance of thrombus from the external and internal iliac veins, intraoperative venography, early ambulation, and religious use of compression stockings. In a prospective randomized study from Sweden comparing surgery with anticoagulation, at 5 years, 37% of operated patients were asymptomatic, compared with just 18% in the anticoagulation group. Vein patency was 77% in the surgical group compared with just 30% in the anticoagulation group.[156]

Table. Surgical Thrombectomy with Temporary Arteriovenous Fistula in Early Iliac Vein Patency[157]



View Table

See Table

Placement of Inferior Vena Cava Filters

Inferior vena cava filters are not recommended in patients with acute venous thromboembolism (VTE) on anticoagulant therapy.[113]  These filters were developed in an attempt to trap emboli and minimize venous stasis. In most patients with deep venous thrombosis (DVT), prophylaxis against the potentially fatal passage of thrombus from the lower extremity or pelvic vein to the pulmonary circulation is adequately accomplished with anticoagulation. An inferior vena cava filter is a mechanical barrier to the flow of emboli larger than 4 mm.

In the past, inferior vena cava filters were placed in 4.4% of patients. Recent use was documented in 14% of patients with DVT; this rate was perhaps due to broadened indications with the introduction of removable filters. Temporary or removable filters, all of which may also be left as permanent, permit transient mechanical pulmonary embolism (PE) prophylaxis. This option may be useful in the setting of polytrauma, head injury, hemorrhagic stroke, known VTE, or major surgery when PE prophylaxis must be maintained during a short-term contraindication to anticoagulation.

In a randomized trial, the addition of an inferior vena cava filter to anticoagulation for DVT increased the risk of recurrent DVT (11.6% to 20.8%) and did not improve the 2-year survival rate. However, the filter group had significantly fewer PEs (1.1% vs 4.8%). Of note was the risk of major bleeding at 3 months (10.5%). This result agrees with other reports and highlights the usual trade-off of prophylaxis with a filter versus anticoagulation and the respective complication risks of new DVT (peripheral to the filter) versus major hemorrhage. In the elderly patient with an increased risk of bleeding, and particularly if the patient is at risk for trauma, the risk and benefits may favor use of a filter.

Catheter-directed thrombolysis does not add to the risk of PE to warrant routine filter placement. However, for patients with contraindications to pharmacologic lysis in whom a percutaneous mechanical thrombectomy device is to be used, a filter may be a useful adjunct.[158]

The ideal vena cava filter would trap venous emboli while maintaining normal venous flow. Many different filter configurations have been used, but the current benchmark remains the Greenfield filter with the longest long-term data. Patency rates greater than 95% and recurrent embolism rates of less than 5% have been demonstrated by numerous studies. The conical shape allows central filling of emboli while allowing blood on the periphery to flow freely. Numerous other filters with similar track records have since been developed, including filters that can be removed.

Regardless of the type of filter placed, the technique remains the same. Local anesthetic is used to anesthetize either the groin for a femoral vein approach or the neck for a jugular vein approach. A single wall needle is used under ultrasonic guidance to enter the target vein, and a 0.035-inch guidewire is passed into the inferior vena cava. A venogram is performed to identify the renal veins and measure the diameter of the vena cava to ensure the cava is not too big for the filter. Intravascular ultrasound (IVUS) can also be used for this purpose. It has the added benefit of not only allowing for bedside filter placement in sick intensive care unit (ICU) patients, but it also obviates the need for IV contrast. The correct filter location traditionally entails an infra-renal fixation with central filter extension to the level of the renal veins. Placement in the suprarenal inferior vena cava or superior vena cava may be indicated in some situations.

American Heart Association recommendations for inferior vena cava filters include the following[10] :

Relative contraindications include the following:

For more information, see Inferior Vena Caval Thrombosis and Inferior Vena Cava Filters.

Replacement of Venous Valves

Percutaneously placed bioprosthetic venous valves are under development and may provide a minimally invasive therapy to the long-term complication of postthrombotic syndrome due to valve destruction. If successful, this approach may provide a percutaneous therapeutic alternative for patients with primarily palliative options to manage their venous reflux symptoms. An effective therapy should diminish one of the primary indications for aggressive thrombolytic therapy for acute deep venous thrombosis.

Use of Elastic Compression Stockings

Postthrombotic syndrome (PTS) affects approximately 50% of patients with deep venous thrombosis (DVT) after 2 years. Elderly patients and patients with recurrent ipsilateral DVT have the highest risk. Below-the-knee elastic compression stockings (ECS) assist the calf muscle pump and reduce venous hypertension and venous valvular reflux. This reduces leg edema, aids the microcirculation, and prevents venous ischemia.

In a randomized controlled study from an Italian university setting involving 180 patients who presented with a first episode of symptomatic proximal DVT, Prandoni and colleagues found below-the-knee ECS to have value for the prevention of PTS. After conventional anticoagulation with heparin, patients were discharged on therapeutic warfarin for 3-6 months and randomly assigned to the control group (no ECS) or the ECS group. Graduated compression stockings with ankle pressures of 30-40 mm Hg were given to the participants, who were required to wear them daily on the affected leg or legs over 2 years. Ninety percent of trial participants were compliant (wore the stockings for at least 80% of daytime hours), and 5-year cumulative data was evaluated to compare the incidence of PTS between the groups.[159]

A standardized validated scale was used to assess symptoms, severity, and/or progression of PTS. PTS occurred in 26% of patients who wore ECS compared with 49% of patients without ECS. All patients with PTS except one developed manifestations of the syndrome within the first 2 years after the initial diagnosis of DVT. The number of patients who need to be treated with ECS was estimated at 4.3 to prevent one case of PTS. The adjusted hazard ratio was 0.49 (CI 0.29-0.84, P = .011) in favor of ECS. Almost 50% of their patients with proximal DVT developed PTS within 2 years.

The regular use of graduated elastic compression stockings reduced the incidence of PTS by 50%. The authors also noted that the benefit conferred by ECS was not related to the rate of recurrent DVT, which was identical in both groups. The authors strongly recommended the early use and widespread implementation of graduated elastic stockings with adequate anticoagulant therapy for symptomatic proximal DVT to prevent the development of PTS.

The Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy observed that PTS occurs in 20-50% of patients with objectively confirmed DVT and assigned a grade 1A recommendation for the use of graduated elastic compression stockings for 2 years after the onset of proximal DVT.[144, 160] With the adoption of outpatient therapy for proximal DVT, the initial management of DVT increasingly becomes the responsibility of the emergency physician.

More recently, the ACCP recommends against the routine use of compression stockings in patients with acute DVT to prevent postthrombotic syndrome.[113]

Ambulation

Controversy exists regarding the role of ambulation in the therapy of deep venous thrombosis (DVT). A study by Partsch reviewed the myths surrounding immediate ambulation and compression in the patient with newly diagnosed DVT and concluded that early ambulation and compression is not associated with any significant risk of pulmonary embolism (PE).[161] It is well recognized from the older literature that almost 50% of patients with acute proximal DVT have evidence, based on V/Q pulmonary scanning, of asymptomatic PE at baseline. Analyzing the effect of ambulation and compression in this patient cohort focused on the development of a new PE, the relief of pain and swelling, and the reduction in the incidence and severity of postthrombotic syndrome (PTS).

The authors cited 2 small previous studies that demonstrated that the incidence of a new PE after initiation of anticoagulant therapy with a low-molecular-weight heparin (LMWH) did not increase significantly in patients treated with early ambulation and compression. They had previously reported their own prospective cohort study of 1289 patients with acute DVT treated as outpatients with LMWH, early ambulation, and compression. Partsch et al reported that only 77 of 1289 patients (5.9%) developed a new PE, only 6 of 1289 patients (0.4%) of these were symptomatic, and only 3 deaths (0.23%) were attributed to the PE. This was not significantly different than historical controls.

A systematic review by Kahn et al found that in patients with acute DVT, early walking exercise is safe and may help to reduce acute symptoms and that in patients with previous DVT, exercise training does not increase leg symptoms acutely and may help to prevent or improve the postthrombotic syndrome.[162]

In Europe, early ambulation and compression has been the mainstay of adjunctive treatment for DVT. In North America, the unsubstantiated fear of dislodging clots by ambulation led clinicians to recommend bed rest and leg elevation to their patients. The authors explained that bed rest promotes venous stasis, which is a major risk factor for DVT and, therefore, may actually enhance thrombus propagation and the risk of subsequent PE.

The authors also cited a number of other studies that revealed a significant decrease in leg swelling (using leg circumference measures) and pain (analog pain scales and quality of life scores) with early ambulation and compression. They also recognized the limited data that are available to assess the effect of early ambulation and compression on the subsequent development of PTS. In their own small trial, they reported a trend toward a lower incidence of PTS. They conceded that a larger, long-term study would be required. Nevertheless, they strongly recommended early ambulation for their patients in addition to elastic compression stockings.

The ACCP Consensus Conference on Antithrombotic and Thrombolytic Therapy for venous thromboembolism also recommended ambulation as tolerated for patients with DVT.[144, 160] Therefore, early ambulation on day 2 after initiation of outpatient anticoagulant therapy in addition to effective compression is strongly recommended. Early ambulation without ECS is not recommended. The fear of dislodging clots and precipitating a fatal PE is unfounded.

Treatment of Superficial Thrombophlebitis

Superficial thrombophlebitis is often associated with deep venous thrombosis (DVT) in two specific settings. The following high-risk groups require further evaluation for DVT:

Uncomplicated superficial thrombophlebitis may be treated symptomatically with heat, nonsteroidal anti-inflammatory agents (NSAIDs), and compression hose. Bed rest is not recommended.

Some centers recommend full anticoagulation for high-risk patients with isolated superficial thrombophlebitis. Some physicians may anticoagulate high-risk patients with negative initial study results until follow-up surveillance studies are completed. An alternative approach involves symptomatic care alone with close follow-up and repeated noninvasive testing in 1 week. Full anticoagulation is then reserved only for those patients with proven proximal vein DVT.

Treatment of Axillary and Subclavian Vein Thrombosis

This was first described by Paget in 1875 and von Schrötter in 1884 and is sometimes referred to as Paget–von Schrötter syndrome. The pathophysiology is similar to that of deep venous thrombosis (DVT), and the etiologies overlap. The incidence is lower than that of lower extremity DVT because of decreased hydrostatic pressure, fewer venous valves, higher rates of blood flow, and less frequent immobility of the upper arm.

Thoracic outlet compression from cervical ribs or congenital webs may precipitate axillary/subclavian venous thrombosis. Catheter-induced thrombosis is increasingly a common cause of this condition. The increased use of subclavian catheters for chemotherapy and parenteral nutrition has resulted in a dramatic increased incidence of proven thrombosis. Similarly, pulmonary artery catheters are associated with a high incidence of internal jugular and subclavian vein thrombosis. Pulmonary embolism (PE) occurs in approximately 10% of patients. Fatal or massive PE is extremely rare.

Ultrasonography and venography are the diagnostic tests of choice. Ultrasonographic findings may be falsely negative because of collateral blood flow. Duplex ultrasonography is accurate for the evaluation of the internal jugular vein and its junction with the subclavian vein where the innominate vein begins.

Thrombolytic therapy is the treatment of choice for axillary/subclavian venous thrombosis. Restoration of venous patency is more critical for the prevention of chronic venous insufficiency in the upper extremity. Thrombolysis is best accomplished with local administration of the thrombolytic agent directly at the thrombus. After completion of a venographic study, a catheter is floated up to the site of the clot, and the thrombolytic agent is administered as a direct infusion. Venographic assessment for clot lysis is repeated every 4-6 hours until venous patency is restored. Heparin is usually given concurrently to prevent rethrombosis.

In the presence of anatomic abnormalities, surgical therapy is recommended to minimize long-term morbidity and recurrence. Catheter-induced thrombosis may require removal of the device. Locally infused thrombolytic agents have been used successfully and are currently the treatment of choice.

Prophylaxis of Deep Venous Thrombosis

Prevention of deep venous thrombosis (DVT) has long been studied in various clinical situations with varying degrees of success. Primary prophylaxis is directed toward acting on one or more components of the Virchow triad, affecting blood flow, coagulation, or vessel wall endothelium. Methods of prophylaxis may be generally divided into mechanical and pharmacologic. Many pharmacologic agents are currently available to prevent thrombosis. Agents that retard or inhibit the process belong under the general heading of anticoagulants. Agents that prevent the growth or formation of thrombi are properly termed antithrombotics and include anticoagulants and antiplatelet drugs, whereas thrombolytic drugs lyse existing thrombi.

Surgical patients undergoing general anesthesia have been extensively studied. Studies of pneumatic compression in cardiac surgery and neurosurgical patients have shown a distinct improvement in the incidence of DVT without the added risk of bleeding.[163, 164] However, the effect is less impressive in higher-risk patients, and compliance can be difficult. Routine use of anticoagulant prophylaxis after cardiac surgery is discouraged.[165]  Kolluri et al showed no benefit of prophylactic postoperative fondaparinux following after coronary artery bypass graft (CABG) surgery.[165]  

Timing and duration of prophylactic agents has also been determined to have a significant effect on the development of DVT. Early prophylaxis in surgical patients with low molecular weight heparin has been associated with significant reductions in postoperative venous thrombosis. If surgery is delayed, then prophylaxis with low-dose unfractionated heparin or low molecular weight heparin should be initiated at the time of admission and discontinued prior to surgery.

Major surgical and high-risk orthopedic procedures place patients at risk for deep venous thrombosis and venous thromboembolism, including pulmonary embolism. Complications of DVT include postphlebitic syndrome or death from pulmonary embolism. Therefore, prophylaxis with anticoagulant medications, as well as the adjunct use of mechanical devices, is essential. The most effective treatment protocol for a patient must be determined on a case-by-case basis and account for the risk-benefit ratio in each situation. A risk stratification protocol, such as that developed by the American College of Chest Physicians (ACCP), is recommended to determine the appropriate level and method of treatment.

For more information, see Deep Venous Thrombosis Prophylaxis.

Diagnosis of Venous Thromboembolism

In November 2018, the American Society of Hematology (ASH) released guidelines for the diagnosis of venous thromboembolism (VTE).[166]  The American Academy of Family Physicians endorsed these guidelines in March 2019 and provided the following key recommendations from the guidelines.[167]

D-dimer testing alone should not be used to rule in or diagnose a PE, and a positive D-dimer alone should not be used to diagnose DVT.

Pulmonary Embolism (PE)

Individuals with a low or intermediate pretest probability or prevalence: Clinicians should use a D-dimer strategy to rule out PE, followed by a ventilation-perfusion (VQ) scan or computed tomography pulmonary angiography (CTPA) in patients requiring additional testing. D-dimer testing alone should not be used to rule in a PE.

Individuals with a high pretest probability or prevalence (≥50%): Clinicians should start with CTPA to diagnose PE. If CTPA is not available, a VQ scan should be used with appropriate follow-up testing.

Individuals with a high pretest probability/prevalence: D-dimer testing alone should not be used to diagnose PE and should not be used as a subsequent test after CT scanning.

Individuals with a positive D-dimer or likely pretest probability: CTPA should be performed. D-dimer testing can be used to exclude recurrent PE in individuals with an unlikely pretest probability.

Outpatients older than 50 years: Use of an age-adjusted D-dimer cutoff is safe and improves the diagnostic yield. Age-adjusted cutoff = Age (years) × 10 µg/L (using D-dimer assays with a cutoff of 500 µg/L).

Lower Extremity (LE) Deep Vein Thrombosis (DVT)

Individuals with a low pretest probability or prevalence: Clinicians should use a D-dimer strategy to rule out DVT, followed by proximal LE or whole-leg ultrasonography in patients requiring additional testing.

Individuals with a low pretest probability or prevalence (≤10%): Positive D-dimer alone should not be used to diagnose DVT, and additional testing following negative proximal or whole-leg ultrasonography should not be conducted.

Individuals with an intermediate pretest probability or prevalence (~25%): Whole-leg or proximal LE ultrasonography should be used. Serial proximal ultrasonographic testing is needed after a negative proximal ultrasonogram. No serial testing is needed after a negative whole-leg ultrasonogram.

Individuals with suspected DVT and a high pretest probability or prevalence (≥50%): Whole-leg or proximal LE ultrasonography should be used. Serial ultrasonography should be used if the initial ultrasonogram is negative and no alternative diagnosis is identified.

Upper Extremity (UE) DVT

Individuals with a low prevalence/unlikely pretest probability: D-dimer testing should be used to exclude UE DVT, followed by duplex ultrasonography if findings are positive.

Individuals with a high prevalence/likely pretest probability: Either D-dimer testing followed by duplex ultrasonography/serial duplex ultrasonography, or duplex ultrasonography/serial duplex ultrasonography alone can be used for assessing patients suspected of having a UE DVT.

A positive D-dimer alone should not be used to diagnose UE DVT.

Anticoagulation for Venous Thromboembolism

The guidelines on optimal management of anticoagulation therapy for venous thromboembolism (VTE) were released on November 7, 2018, by the American Society of Hematology (ASH).[168]

Initial Anticoagulant Dose Selection

In obese patients receiving low-molecular-weight heparin (LMWH) for treatment of acute VTE, it is suggested that initial LMWH dose selection be based on actual body weight rather than on a fixed maximum daily dose (ie, capped dose).

Drug-Interaction Management

For patients requiring administration of inhibitors or inducers of P-glycoprotein (P-gp) or strong inhibitors or inducers of cytochrome P450 (CYP) enzymes, it is suggested to use an alternative anticoagulant (eg, a vitamin K antagonist [VKA] or LMWH) rather than a direct oral anticoagulant (DOAC) to treat VTE.

Point-of-Care INR Testing

For patients receiving maintenance VKA therapy for VTE, home point-of-care international normalized ratio (INR) testing (patient self-testing [PST]) is suggested in preference to any other INR testing approach except patient self-management (PSM) in suitable patients (those who have demonstrated competency to perform PST and who can afford this option).

For patients receiving maintenance VKA therapy for VTE, point-of-care INR testing by the patient at home with self-adjustment of VKA dose (PSM) is suggested in preference to any other management approach, including PST in suitable patients (those who have demonstrated competency to perform PSM and who can afford this option).

Selection of Timing Between INR Measurements (INR Recall Interval)

For patients receiving VKA therapy for VTE, an INR recall interval of 4 weeks or less is suggested rather than an interval longer than 4 weeks after VKA dose adjustment due to an out-of-target-range INR.

For patients receiving maintenance VKA therapy for VTE, a longer (6-12 weeks) INR recall interval is suggested rather than a shorter (4 weeks) interval during periods of stable INR control.

Laboratory Monitoring of Anticoagulant Response

For patients with renal dysfunction (creatinine clearance, < 30 mL/min) or obesity receiving LMWH therapy for VTE, it is suggested not to use anti–factor Xa concentration monitoring to guide LMWH dose adjustment.

For patients receiving DOAC therapy for VTE, it is suggested not to measure the DOAC anticoagulant effect during management of bleeding.

Transitions Between Anticoagulants

For patients transitioning from DOAC to VKA, overlapping DOAC and VKA therapy until the INR is within the therapeutic range is suggested in preference to LMWH or unfractionated heparin (UFH) "bridging therapy."

Use of Specialized AMS

For patients receiving anticoagulation therapy for VTE, specialized anticoagulation-management service (AMS) care is suggested in preference to care provided by the patient's usual healthcare provider.

Structured Patient Education

For patients receiving oral anticoagulation therapy for VTE, supplementary patient education is suggested in addition to basic education.

Efforts to Improve Adherence to Anticoagulant Regimen

For patients receiving anticoagulation therapy for VTE, it is suggested not to use a daily lottery, electronic reminders, or a combination of the two to improve medication adherence. It is also suggested not to use visual medication schedules (provided to patients at each visit, along with brief counseling) to improve medication adherence.

Invasive Procedure Management

For patients at low-to-moderate risk for recurrent VTE who require interruption of VKA therapy for invasive procedures, VKA interruption alone is recommended in preference to periprocedural bridging with LMWH or UHF.

For patients interrupting DOAC therapy for scheduled invasive procedures, it is suggested not to perform laboratory testing for DOAC effect before procedures.

Excessive Anticoagulation and Bleeding Management

For patients receiving VKA therapy for VTE with INR >4.5 but < 10 and without clinically relevant bleeding, temporary cessation of VKA alone is suggested, without the addition of vitamin K.

For patients with life-threatening bleeding during VKA therapy for VTE and an elevated INR, use of four-factor prothrombin complex concentrates (PCCs) is suggested in preference to fresh frozen plasma (FFP) as an addition to cessation of VKA and IV vitamin K.

For patients with life-threatening bleeding during oral direct Xa inhibitor therapy for VTE, it is suggested to use either four-factor PCC administration as an addition to cessation of oral direct Xa inhibitor or cessation of oral direct Xa inhibitor alone.

For patients with life-threatening bleeding during oral direct Xa inhibitor therapy for VTE, it is suggested to use coagulation factor Xa (recombinant), inactivated-zhzo in addition to cessation of oral direct Xa inhibitor rather than no coagulation factor Xa (recombinant), inactivated-zhzo.

For patients with life-threatening bleeding during dabigatran therapy for VTE, it is suggested to use idarucizumab in addition to cessation of dabigatran rather than no idarucizumab.

For patients with life-threatening bleeding during LMWH or UFH therapy for VTE, it is suggested to use protamine in addition to LMWH/UFH cessation rather than no protamine.

Anticoagulant Resumption Following Bleeding

For patients receiving anticoagulation therapy for VTE who survive an episode of major bleeding, resumption of oral anticoagulation therapy within 90 days is suggested in preference to discontinuance of oral anticoagulation therapy.

Medication Summary

The goals of pharmacotherapy for deep venous thrombosis (DVT) are to reduce morbidity, to prevent the postthrombotic syndrome (PTS), and to prevent pulmonary embolism (PE), all with minimal adverse effects and cost. The main agent classes include anticoagulants and thrombolytics.[169]

Rivaroxaban (Xarelto)

Clinical Context:  Rivaroxaban is an oral factor Xa inhibitor that inhibits platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It is indicated for a variety of treatment and prophylaxis VTE indications including the following:

Risk reduction of stroke and systemic embolism in nonvalvular atrial fibrillation

Treatment of DVT

Treatment of PE

Reduction in risk of recurrent DVT and/or PE

Prophylaxis of DVT following hip or knee replacement surgery

Prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications owing to restricted mobility (and who are not at high risk of bleeding)

Risk reduction of major CV events with CAD or PAD

Apixaban (Eliquis)

Clinical Context:  Apixaban is an oral factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It inhibits free and clot-bound factor Xa, and prothrombinase activity; no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. It is indicated for prophylaxis of deep venous thrombosis (DVT) or pulmonary embolism (PE) in adults undergoing knee or hip replacement surgery. It is also indicated for treatment of DVT and PE and for prevention of recurrence (following the initial 6 months of the initial treatment).

Dabigatran (Pradaxa)

Clinical Context:  Dabigatran inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It is indicated for the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation (NVAF). This agent is also indicated for the prevention and treatment of deep venous thrombosis (DVT) or pulmonary embolism (PE).

Edoxaban (Savaysa)

Clinical Context:  Edoxaban is indicated to reduce the risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation (NVAF). 

Betrixaban (Bevyxxa)

Clinical Context:  Betrixaban is indicated for the prophylaxis of venous thromboembolism (VTE) in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE.

Fondaparinux sodium (Arixtra)

Clinical Context:  Fondaparinux sodium is a synthetic anticoagulant that works by inhibiting factor Xa, a key component involved in blood clotting. It provides a highly predictable response and has a bioavailability of 100%. The drug has a rapid onset of action and a half-life of 14-16 hours, allowing for sustained antithrombotic activity over 24-hour period. Fondaparinux sodium does not affect prothrombin time or activated partial thromboplastin time, nor does it affect platelet function or aggregation.

Heparin

Clinical Context:  Heparin augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents reaccumulation of a clot after a spontaneous fibrinolysis.

Class Summary

These agents prevent recurrent or ongoing thrombolytic occlusion of the vertebrobasilar circulation.

Dalteparin (Fragmin)

Clinical Context:  Dalteparin enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases inhibition of factor Xa. Except in overdoses, no utility exists in checking prothrombin time (PT) or activated partial thromboplastin time (aPTT) because aPTT does not correlate with anticoagulant effect of fractionated low-molecular-weight heparin (LMWH). The average duration of treatment is 7-14 days.

Enoxaparin (Lovenox)

Clinical Context:  Enoxaparin is a low-molecular-weight (LMWH) used in treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) as well as DVT prophylaxis. It enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity, it slightly affects thrombin and clotting time, and it preferentially increases inhibition of factor Xa. The average duration of treatment is 7-14 days.

Tinzaparin (Innohep)

Clinical Context:  Tinzaparin enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases inhibition of factor Xa. The average duration of treatment is 7-14 days.

Class Summary

Low-molecular-weight-heparin (LMWH) is prepared by selectively treating unfractionated heparin (UFH) to isolate the low molecular weight (<9000 Da) fragments. Its activity is measured in units of factor X inactivation, and monitoring of the activated partial thromboplastin time (aPTT) is not required. The dose is weight adjusted. Enoxaparin (Fragmin), dalteparin (Lovenox), and tinzaparin (Innohep) have received US Food and Drug Administration (FDA) approval for the treatment of deep venous thrombosis (DVT) in the United States. Enoxaparin is approved for inpatient and outpatient treatment of DVT.

Warfarin (Coumadin)

Clinical Context:  Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism (PE), and thromboembolic disorders. The dose must be individualized and adjusted to maintain an international normalized ratio (INR) of 2-3.

Class Summary

Coumarins are a class of oral anticoagulant drugs that act as antagonists to vitamin K. The mechanism of action is to interfere with the interaction between vitamin K and coagulation factors II, VII, IX, and X. Vitamin K acts as a cofactor at these levels. Coumarins produce their anticoagulant effect by inhibiting the carboxylation necessary for biologic activity.

Tenecteplase (TNKase)

Clinical Context:  Tenecteplase is a modified version of alteplase (tPA) made by substituting 3 amino acids of alteplase. It has a longer half-life and, thus, can be given as a single bolus over 5 seconds infusion instead of 90 minutes with alteplase. It appears to cause less non-intracranial bleeding but has similar risk of intracranial bleeding and stroke as alteplase. The dose should be determined on the basis of patient weight. Treatment should be initiated as soon as possible after onset of acute myocardial infarction symptoms. Because tenecteplase contains no antibacterial preservatives, it must be reconstituted immediately before use.

Alteplase, tPA (Activase)

Clinical Context:  Alteplase is a thrombolytic agent for deep venous thrombosis (DVT) or pulmonary embolism (PE). It is a tissue plasminogen activator (tPA) produced by recombinant DNA and used in the management of acute myocardial infarction, acute ischemic stroke, and PE. The safety and efficacy of this regimen with coadministration of heparin and aspirin during the first 24 hours after symptom onset have not been investigated.

Reteplase (Retavase)

Clinical Context:  Reteplase is a tissue plasminogen activator (tPA) produced by recombinant DNA and used in the management of acute myocardial infarction, acute ischemic stroke, and pulmonary embolism (PE). Heparin and aspirin are usually given concomitantly and after reteplase.

Class Summary

These agents are used to dissolve a pathologic intraluminal thrombus or embolus that has not been dissolved by the endogenous fibrinolytic system. Also used for the prevention of recurrent thrombus formation and rapid restoration of hemodynamic disturbances.

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for endovascular intervention for deep venous thrombosis (DVT)?Which devices are an adjunct therapy to catheter-directed thrombolysis for deep venous thrombosis (DVT)?What is the role of surgical thrombectomy in the treatment of deep venous thrombosis (DVT)?What is the protocol for surgical thrombectomy?What is used to reduce the risk of embolization during a surgical thrombectomy for deep venous thrombosis (DVT)?What is the benefit of creating an arteriovenous fistula during surgical thrombectomy for deep venous thrombosis (DVT)?What are the rethrombosis rates in surgical thrombectomy for deep venous thrombosis (DVT)?When are IVC filters contraindicated in the treatment of deep venous thrombosis (DVT)?What is the role of IVC filters in the treatment of deep venous thrombosis (DVT)?What is the efficacy of adding an IVC filter to anticoagulation in the treatment of deep venous thrombosis (DVT)?When is an IVC filter a useful adjunct in the treatment of deep venous thrombosis (DVT)?What is the ideal vena cava filter for treatment of deep venous thrombosis (DVT)?Which techniques are used for the placement of IVC filters in the treatment of deep venous thrombosis (DVT)?What are the AHA recommendations for use of IVC filters in the treatment of deep venous thrombosis (DVT)?What are relative contraindications for IVC filters in the treatment of deep venous thrombosis (DVT)?What is the role of percutaneously placed bioprosthetic venous valves in the treatment of deep venous thrombosis (DVT)?What is the role of elastic compression stockings (ECS) in the treatment of deep venous thrombosis (DVT)?What is the efficacy of elastic compression stockings (ECS) for the prevention of postthrombotic syndrome (PTS) in patients with deep venous thrombosis (DVT)?How much has the use of graduated elastic compression stockings (ECS) reduced the incidence of postthrombotic syndrome (PTS) in patients with deep venous thrombosis (DVT)?What are the ACCP recommendations for the use of elastic compression stockings (ECS) in patients with deep venous thrombosis (DVT)?What is the role of ambulation in the therapy of deep venous thrombosis (DVT)?What is the role of walking exercise in the treatment of deep venous thrombosis (DVT)?When is ambulation used in the treatment of deep venous thrombosis (DVT)?What are the ACCP recommendations for the use of ambulation in deep venous thrombosis (DVT) treatment?When is superficial thrombophlebitis associated with deep venous thrombosis (DVT)?How is superficial thrombophlebitis treated?What is axillary and subclavian vein thrombosis (Paget–von Schrötter syndrome)?How is axillary and subclavian vein thrombosis (Paget–von Schrötter syndrome) diagnosed?What are the treatment options for axillary and subclavian vein thrombosis (Paget–von Schrötter syndrome)?When is surgery indicated for axillary and subclavian vein thrombosis (Paget–von Schrötter syndrome)?What are the options for primary prophylaxis of deep venous thrombosis (DVT)?What is the efficacy of pneumatic compression in preventing deep venous thrombosis (DVT) in patients undergoing cardiac surgery or neurosurgery?What is the effect of timing and duration of prophylactic agents on the development of deep venous thrombosis (DVT)?Which factors increase the risk for deep venous thrombosis (DVT) and what are the possible complications?What are the goals of pharmacotherapy for deep venous thrombosis (DVT)?Which medications in the drug class Anticoagulants are used in the treatment of Deep Venous Thrombosis (DVT)?Which medications in the drug class Low Molecular Weight Heparins are used in the treatment of Deep Venous Thrombosis (DVT)?Which medications in the drug class Vitamin K Antagonists are used in the treatment of Deep Venous Thrombosis (DVT)?Which medications in the drug class Thrombolytics are used in the treatment of Deep Venous Thrombosis (DVT)?

Author

Kaushal (Kevin) Patel, MD, Vascular Surgeon, Kaiser Permanente Los Angeles Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Linda Jun Chun, MD, Vascular and Endovascular Surgeon, Kaiser Permanente, Los Angeles Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director for Emergency Medicine, Sanz Laniado Medical Center, Netanya, Israel

Disclosure: Nothing to disclose.

Additional Contributors

Jason S Chang, MD, Clinical Instructor, Department of Emergency Medicine, University of Pittsburgh Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Marc D Basson, MD, PhD, MBA, FACS Professor, Chair, Department of Surgery, Assistant Dean for Faculty Development in Research, Michigan State University College of Human Medicine

Marc D Basson, MD, PhD, MBA, FACS is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Gastroenterological Association, Phi Beta Kappa, and Sigma Xi

Disclosure: Nothing to disclose.

John J Borsa, MD Consulting Staff, Department of Radiology, St Joseph Medical Center

John J Borsa, MD is a member of the following medical societies: American College of Radiology, American Society of Neuroradiology, Cardiovascular and Interventional Radiological Society of Europe, Radiological Society of North America, Royal College of Physicians and Surgeons of Canada, and Society of Interventional Radiology

Disclosure: Nothing to disclose.

Hearns W Charles, MD Assistant Professor of Radiology, New York University School of Medicine; Attending Physician, Division of Vascular and Interventional Radiology, Department of Radiology, New York University Medical Center

Hearns W Charles, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, Radiological Society of North America, and Society of Cardiovascular and Interventional Radiology

Disclosure: Nothing to disclose.

Kyung J Cho, MD, FACR William Martel Professor of Radiology, Interventional Radiology Fellowship Director, University of Michigan Health System

Kyung J Cho, MD, FACR is a member of the following medical societies: American College of Radiology, American Heart Association, American Medical Association, American Roentgen Ray Society, Association of University Radiologists, and Radiological Society of North America

Disclosure: Nothing to disclose.

Douglas M Coldwell, MD, PhD Professor of Radiology, Director, Division of Vascular and Interventional Radiology, University of Louisville School of Medicine

Douglas M Coldwell, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American College of Radiology, American Heart Association, American Physical Society, American Roentgen Ray Society, Society of Cardiovascular and Interventional Radiology, Southwest Oncology Group, and Special Operations Medical Association

Disclosure: Sirtex, Inc. Consulting fee Speaking and teaching; DFINE, Inc. Honoraria Consulting

Francis Counselman, MD, FACEP Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical School

Francis Counselman, MD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, Association of Academic Chairs of Emergency Medicine (AACEM), Norfolk Academy of Medicine, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Paul E Di Cesare, MD, FACS Professor and Chair, Department of Orthopedic Sugery, University of California, Davis, School of Medicine

Paul E Di Cesare, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, and Sigma Xi

Disclosure: Stryker Consulting fee Consulting

Robert S Ennis, MD, FACS Associate Professor, Department of Orthopedic Surgery, University of Miami School of Medicine; President, OrthoMed Consulting Services, Inc

Robert S Ennis, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, and Florida Orthopaedic Society

Disclosure: Nothing to disclose.

Craig F Feied, MD, FACEP, FAAEM, FACPh Professor of Emergency Medicine, Georgetown University School of Medicine; General Manager, Microsoft Enterprise Health Solutions Group

Disclosure: Nothing to disclose.

Luis G Fernandez, MD, KHS, FACS, FASAS, FCCP, FCCM, FICS Assistant Clinical Professor of Surgery and Family Practice, University of Texas Health Science Center; Adjunct Clinical Professor of Medicine and Nursing, University of Texas, Arlington; Chairman, Division of Trauma Surgery and Surgical Critical Care, Chief of Trauma Surgical Critical Care Unit, Trinity Mother Francis Health System; Brigadier General, Texas Medical Rangers, TXSG/MB

Luis G Fernandez, MD, KHS, FACS, FASAS, FCCP, FCCM, FICS is a member of the following medical societies: American Association for the Surgery of Trauma, American College of Chest Physicians, American College of Legal Medicine, American College of Surgeons, American Society of Abdominal Surgeons, American Society of General Surgeons, American Society of General Surgeons, American Society of Law, Medicine & Ethics, American Trauma Society, Association for SurgicalEducation, Association of Military Surgeons of the US, Chicago Medical Society, Illinois State Medical Society, International College of Surgeons, New York Academy of Sciences, Pan American Trauma Society, Society of Critical Care Medicine, Society of Laparoendoscopic Surgeons, Southeastern Surgical Congress, Texas Medical Association, and Undersea and Hyperbaric Medical Society

Disclosure: Nothing to disclose.

Douglas M Geehan, MD Associate Professor, Department of Surgery, University of Missouri at Kansas City

Douglas M Geehan, MD is a member of the following medical societies: American College of Surgeons, American Institute of Ultrasound in Medicine, American Medical Association, Association for Academic Surgery, Phi Beta Kappa, Society of American Gastrointestinal and Endoscopic Surgeons, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

John Geibel, MD, DSc, MA Vice Chair and Professor, Department of Surgery, Section of Gastrointestinal Medicine, and Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director, Surgical Research, Department of Surgery, Yale-New Haven Hospital

John Geibel, MD, DSc, MA is a member of the following medical societies: American Gastroenterological Association, American Physiological Society, American Society of Nephrology, Association for Academic Surgery, International Society of Nephrology, New York Academy of Sciences, and Society for Surgery of the Alimentary Tract

Disclosure: AMGEN Royalty Consulting; ARdelyx Ownership interest Board membership

Harris Gellman, MD Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami, Leonard M Miller School of Medicine

Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, and Arkansas Medical Society

Disclosure: Nothing to disclose.

Craig Greben, MD Assistant Professor of Radiology, Hofstra University School of Medicine; Chief, Division of Vascular and Interventional Radiology, North Shore University Hospital

Craig Greben, MD is a member of the following medical societies: Society of Cardiovascular and Interventional Radiology

Disclosure: Nothing to disclose.

Lars Grimm, MD, MHS House Staff, Department of Diagnostic Radiology, Duke University Medical Center

Disclosure: Nothing to disclose.

Michael A Grosso, MD Consulting Staff, Department of Cardiothoracic Surgery, St Francis Hospital

Michael A Grosso, MD is a member of the following medical societies: American College of Surgeons, Society of Thoracic Surgeons, and Society of University Surgeons

Disclosure: Nothing to disclose.

George Hartnell, MBChB Professor of Radiology, Tufts University School of Medicine; Director of Cardiovascular and Interventional Radiology, Department of Radiology, Baystate Medical Center

George Hartnell, MBChB is a member of the following medical societies: American College of Cardiology, American College of Radiology, American Heart Association, Association of University Radiologists, British Institute of Radiology, British Medical Association, Massachusetts Medical Society, Radiological Society of North America, Royal College of Physicians, Royal College of Radiologists, andSociety of Cardiovascular and Interventional Radiology

Disclosure: Nothing to disclose.

Eric K Hoffer, MD Director, Vascular and Interventional Radiology, Associate Professor of Radiology, Section of Angiography and Interventional Radiology, Dartmouth-Hitchcock Medical Center

Eric K Hoffer, MD is a member of the following medical societies: American Heart Association, Radiological Society of North America, Society for Cardiac Angiography and Interventions, and Society of Interventional Radiology

Disclosure: Nothing to disclose.

James Quan-Yu Hwang, MD, RDMS, RDCS, FACEP Staff Physician, Emergency Department, Kaiser Permanente

James Quan-Yu Hwang, MD, RDMS, RDCS, FACEP is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Institute of Ultrasound in Medicine, and Society for Academic Emergency Medicine

Disclosure: 3rd Rock Ultrasound, LLC Salary Speaking and teaching; Schlesinger Associates Consulting fee Consulting; Philips Ultrasound Consulting fee Consulting

Bartholomew Kwan, MBBS, FRCPC, FRCR Staff Radiologist, Department of Medical Imaging, WOHC Brampton Civic Hospital

Bartholomew Kwan, MBBS, FRCPC, FRCR is a member of the following medical societies: American Roentgen Ray Society, Cardiovascular and Interventional Radiological Society of Europe, Radiological Society of North America, Royal College of Physicians and Surgeons of Canada, Royal College of Radiologists, and Society of Interventional Radiology

Disclosure: Nothing to disclose.

William C Manson, MD Director of Emergency Ultrasound, Department of Emergency Medicine, Emory University School of Medicine

William C Manson, MD is a member of the following medical societies: American College of Emergency Physicians, American Institute of Ultrasound in Medicine, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine

Disclosure: The Emergency Ultrasound Course Honoraria Speaking and teaching

Girish R Mood, MBBS, MD, MRCS Fellow, Department of Vascular Medicine, Cleveland Clinic Foundation

Disclosure: Nothing to disclose.

James Naidich, MD Residency Director, North Shore University Hospital; Professor, Department of Radiology, New York University School of Medicine

Disclosure: Nothing to disclose.

Jason J Naidich, MD Assistant Professor of Radiology, New York University School of Medicine; Attending Physician, Division of Vascular and Interventional Radiology, North Shore University Hospital

Disclosure: Nothing to disclose.

Vincent Lopez Rowe, MD Associate Professor of Surgery, Department of Surgery, Division of Vascular Surgery, University of Southern California Medical Center

Vincent Lopez Rowe, MD is a member of the following medical societies: American College of Surgeons, American Heart Association, Pacific Coast Surgical Association, Peripheral Vascular Surgery Society, Society for Clinical Vascular Surgery, Society for Vascular Surgery, and Western Vascular Surgical Society

Disclosure: Nothing to disclose.

Miguel A Schmitz, MD Consulting Surgeon, Department of Orthopedics, Klamath Orthopedic and Sports Medicine Clinic

Miguel A Schmitz, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Orthopaedic Society for Sports Medicine, Arthroscopy Association of North America, and North American Spine Society

Disclosure: Nothing to disclose.

Donald Schreiber, MD, CM Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine

Donald Schreiber, MD, CM is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Abbott Point of Care Inc Research Grant and Speakers Bureau Speaking and teaching; Nanosphere Inc Grant/research funds Research; Singulex Inc Grant/research funds Research; Abbott Diagnostics Inc Grant/research funds None

William A Schwer, MD Professor, Department of Family Medicine, Rush Medical College; Chairman, Department of Family Medicine, Rush-Presbyterian-St Luke's Medical Center

William A Schwer, MD is a member of the following medical societies: American Academy of Family Physicians

Disclosure: Nothing to disclose.

Gary Setnik, MD Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School

Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine

Disclosure: SironaHealth Salary Management position; South Middlesex EMS Consortium Salary Management position; ProceduresConsult.com Royalty Other

Gary P Siskin, MD Professor and Chairman, Department of Radiology, Albany Medical College

Gary P Siskin, MD is a member of the following medical societies: American College of Radiology, Cardiovascular and Interventional Radiological Society of Europe, Radiological Society of North America, and Society of Interventional Radiology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Wai Hong Wilson Tang, MD Associate Professor of Medicine, Section of Heart Failure and Cardiac Transplantation Medicine, Cleveland Clinic Foundation

Wai Hong Wilson Tang, MD is a member of the following medical societies: American College of Cardiology, American Heart Association, Heart Failure Society of America, and International Society for Heart and Lung Transplantation

Disclosure: Abbott Laboratories Grant/research funds Research Supplies; Medtronic Inc Consulting fee Consulting; St Jude Medical Consulting fee Consulting

Anthony Watkinson, MD Professor of Interventional Radiology, The Peninsula Medical School; Consultant and Senior Lecturer, Department of Radiology, The Royal Devon and Exeter Hospital, UK

Anthony Watkinson, MD is a member of the following medical societies: Radiological Society of North America, Royal College of Radiologists, and Royal College of Surgeons of England

Disclosure: Nothing to disclose.

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Deep venous thrombosis (DVT). The computed tomography venogram shows bilateral deep venous thrombosis (arrows).

Deep venous thrombosis (DVT). The image shows venous thrombi.

Deep venous thrombosis (DVT). A pulmonary embolus is shown.

Deep venous thrombosis (DVT). The coagulation pathway is shown.

Deep venous thrombosis (DVT). This chart shows postoperative antithrombin III levels.

Deep venous thrombosis (DVT). This chart depicts perioperative antithrombin III levels and DVT formation.

Deep venous thrombosis (DVT). This lower-extremity venogram shows outlining of an DVT in the popliteal vein with contrast enhancement.

Deep venous thrombosis (DVT). The lower-extremity venogram reveals a nonocclusive chronic thrombus. The superficial femoral vein (lateral vein) has the appearance of two parallel veins, when in fact it is one lumen containing a chronic linear thrombus. Although the chronic clot is not obstructive after it recanalizes, it effectively causes the venous valves to adhere in an open position, predisposing the patient to reflux in the involved segment.

Deep venous thrombosis (DVT). This contrast-enhanced study was obtained through a Mediport placed through the chest wall through the internal jugular vein to facilitate chemotherapy. A thrombus has propagated peripherally from the tip of the catheter in the superior vena cava into both subclavian veins.

Deep venous thrombosis (DVT). Superior vena cava syndrome is noted in a patient with lung cancer. The computed tomography scan demonstrates a hypoattenuating thrombus that fills the superior vena cava. The patient was treated with anticoagulation alone.

Deep venous thrombosis (DVT). Lung scans are shown. LPO = left posterior oblique.

Deep venous thrombosis (DVT). Spiral computed tomography scan showing a pulmonary thrombus.

Deep venous thrombosis (DVT). This is the appearance of a normal pulmonary angiogram.

Deep venous thrombosis (DVT). This is a positive pulmonary angiogram.

Deep venous thrombosis (DVT). This longitudinal ultrasonographic image reveals a partially recanalized thrombus in the femoral vein at the mid thigh.

Deep venous thrombosis (DVT). Note the principal deep veins of the lower extremity.

Deep venous thrombosis (DVT). This image demonstrates postphlebitic chronic venous insufficiency with ulceration.

Deep venous thrombosis (DVT). This image depicts lipodermatosclerosis caused by DVT.

Deep venous thrombosis (DVT). There is a substantial mortality benefit for fibrinolytic therapy compared to anticoagulation in patients with right ventricular strain from pulmonary embolism (Konstantinides, 1997).

Deep venous thrombosis (DVT). These sequential images demonstrate treatment of iliofemoral DVT due to May-Thurner (Cockett) syndrome. Far left: View of the entire pelvis reveals iliac occlusion. Middle left: After 12 hours of catheter-directed thrombolysis, an obstruction at the left common iliac vein is evident. Middle right: After 24 hours of thrombolysis, a bandlike obstruction is seen; this is the impression made by the overlying right common iliac artery. Far right: After stent placement, the image shows wide patency and rapid flow through the previously obstructed region. Note that the patient is in the prone position in all views. (Right and left are reversed.)

Deep venous thrombosis (DVT). This lower-extremity venogram shows outlining of an DVT in the popliteal vein with contrast enhancement.

Deep venous thrombosis (DVT). The lower-extremity venogram reveals a nonocclusive chronic thrombus. The superficial femoral vein (lateral vein) has the appearance of two parallel veins, when in fact it is one lumen containing a chronic linear thrombus. Although the chronic clot is not obstructive after it recanalizes, it effectively causes the venous valves to adhere in an open position, predisposing the patient to reflux in the involved segment.

Deep venous thrombosis (DVT). Two views of a commercially available thrombectomy device are shown. The Helix Clot Buster works by creating a vortex with a spinning self-contained propeller that macerates the clot. No thrombolytic agent (ie, tissue plasminogen activator) is necessary when this device is used, but adjunct thrombolytic medications can be useful. Competing devices are available from other manufacturers.

Deep venous thrombosis (DVT). Popliteal vein thrombosis with normal compression of the common femoral vein is demonstrated. Image courtesy of Very Special Images with permission from Dr Lennard A Nadalo.

Deep venous thrombosis (DVT). Bilateral popliteal vein thrombosis with normal compression of the superficial femoral vein is shown. Image courtesy of Very Special Images with permission from Dr Lennard A Nadalo.

Deep venous thrombosis (DVT). Popliteal vein thrombosis is depicted by a Duplex sonogram showing absent flow. Image courtesy of Very Special Images with permission from Dr Lennard A Nadalo.

Deep venous thrombosis (DVT). Popliteal vein thrombosis is demonstrated by gray-scale images showing compression failure. Image courtesy of Very Special Images with permission from Dr Lennard A Nadalo.

Deep venous thrombosis (DVT). This contrast-enhanced study was obtained through a Mediport placed through the chest wall through the internal jugular vein to facilitate chemotherapy. A thrombus has propagated peripherally from the tip of the catheter in the superior vena cava into both subclavian veins.

Deep venous thrombosis (DVT). Superior vena cava syndrome is noted in a patient with lung cancer. The computed tomography scan demonstrates a hypoattenuating thrombus that fills the superior vena cava. The patient was treated with anticoagulation alone.

Deep venous thrombosis (DVT). The image shows venous thrombi.

Deep venous thrombosis (DVT). A pulmonary embolus is shown.

Deep venous thrombosis (DVT). The coagulation pathway is shown.

Deep venous thrombosis (DVT). This chart shows postoperative antithrombin III levels.

Deep venous thrombosis (DVT). This chart depicts perioperative antithrombin III levels and DVT formation.

Deep venous thrombosis (DVT). Lung scans are shown. LPO = left posterior oblique.

Deep venous thrombosis (DVT). Spiral computed tomography scan showing a pulmonary thrombus.

Deep venous thrombosis (DVT). This is the appearance of a normal pulmonary angiogram.

Deep venous thrombosis (DVT). This is a positive pulmonary angiogram.

Deep venous thrombosis (DVT). The time course of DVT risk is shown in patients not undergoing treatment for total hip replacement (THR).

Deep venous thrombosis (DVT). The computed tomography venogram shows bilateral deep venous thrombosis (arrows).

Deep venous thrombosis (DVT). The high-probability perfusion lung scan shows segmental perfusion defects in the right upper lobe and subsegmental perfusion defects in right lower lobe, left upper lobe, and left lower lobe.

Deep venous thrombosis (DVT). A normal ventilation scan will make the defects noted in the previous image a mismatch and, hence, a high-probability ventilation-perfusion scan.

Deep venous thrombosis (DVT). Anterior views of perfusion and ventilation scans are shown. A perfusion defect is present in the left lower lobe, but perfusion to this lobe is intact, making this a high-probability scan.

Deep venous thrombosis (DVT). A segmental ventilation perfusion mismatch is evident in a left anterior oblique projection.

Deep venous thrombosis (DVT). This sequence of colored digitized pulmonary angiograms (x-ray) in the front view of the pulmonary arteries in a 43-year-old male patient after a heart attack (cardiac arrest) reveals the presence of a pulmonary embolism with a massive thrombus (clot, dark) in the right and left pulmonary arteries. An outline of the lungs are seen. Image courtesy of Science Source/Zephyr.

Deep venous thrombosis (DVT). Hematoxylin and eosin stain. This is a low-power view of a thrombus composed of platelets, fibrin, and leukocytes.

Study and Number of Patients Patent Iliac Vein
Delin (13)85%
Plate (31)87%
Piquet (92)80%
Einarsson (51)88%
Juhan (42)93%
Vollmar (93)82%
Kniemeyer (185)96%
Neglen (48)89%
  
Total (555)88%