DEEP VENOUS THROMBOSIS & THROMBOPHLEBITIS

Introduction
Background

Deep venous thrombosis (DVT) and its sequela, pulmonary embolism (PE), are the leading causes of preventable in-hospital mortality in the United States. Although PE itself is discussed in other articles, it occurs primarily as a complication of DVT.

The earliest known reference to peripheral venous disease is found on the Ebers 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. Heparin was introduced into clinical practice in 1937. Over the last 25 years, the pathophysiology of DVT has become much better understood, and considerable progress has been made in its diagnosis and treatment.
Pathophysiology

The Virchow triad of venous stasis, vessel wall injury, and hypercoagulable state is still considered the primary mechanism for the development of venous thrombosis. The relative importance of each factor remains a topic of debate, however. The formation, propagation, and dissolution of venous thrombi represent a balance between thrombogenesis and the body's protective mechanisms, specifically the circulating inhibitors of coagulation and the fibrinolytic system.

In practical terms, the development of venous thrombosis is best understood as the activation of coagulation in areas of reduced blood flow. This explains why the most successful prophylactic regimens are anticoagulation and minimization of venous stasis. DVT of the lower extremity usually begins in the deep veins of the calf around the valve cusps or within the soleal plexus. A minority of cases arise primarily in the ileofemoral system as a result of direct vessel wall injury, such as from hip surgery or intravenous catheters.

The vast majority of calf vein thrombi dissolve completely without therapy. Approximately 20% propagate proximally. Propagation usually occurs before embolization. The process of adherence and organization of a venous thrombus does not begin until 5-10 days after thrombus formation. Until this process has been established fully, the nonadherent disorganized thrombus may propagate and/or embolize.

Not all venous thrombi pose equal embolic risk. Studies have shown that isolated calf vein thrombi carry a limited risk of PE. Furthermore, studies have suggested that isolated calf vein thrombi are smaller and do not cause significant morbidity or mortality if they embolize. Contradictory evidence from several other studies has indicated that isolated calf vein thrombi do embolize, suggesting that proximal propagation may occur rapidly and that fatal PE arising from isolated calf vein DVT is a significant risk.

The current diagnostic and therapeutic management of DVT is strongly influenced by the different risks assigned to proximal and calf vein thrombi. The propagation and organization of the venous thrombus usually result in destruction of venous valves and produce varying degrees of venous outflow obstruction. Spontaneous lysis and complete recanalization of established proximal DVT occurs in fewer than 10% of patients, even with anticoagulation. These factors are the most important pathogenic mechanisms in the development of chronic venous insufficiency.
Frequency
United States

The exact incidence of DVT is unknown because most studies are limited by the inherent inaccuracy of clinical diagnosis. More importantly, most DVT is occult and usually resolves spontaneously without complication. 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 will develop a DVT in the course of his or her lifetime. About 600,000 hospitalizations per year occur for DVT in the United States.

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 this data reveals that as many as 5 million people have venous stasis and varying degrees of venous insufficiency.

Mortality/Morbidity

Death from deep venous thrombosis (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 who were followed for 7.6 years.2

* The age-standardized incidence of first-time venous thromboembolism (VTE) is 1.92 per 1000 person-years.
* The incidence of VTE is higher in men than in women and increases with age in both sexes.
* Of the 366 VTE events in this cohort, most of the 191 cases of secondary VTE were associated with more than one underlying condition. These included cancer (48%), hospitalization (52%), surgery (42%), and major trauma (6%). No antecedent trauma, surgery, immobilization, or diagnosis of cancer was noted in 48% of cases.

In the MEDENOX study3 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:

* Presence of an acute infectious disease
* Age >75 years
* Cancer
* History of prior VTE

The principal long-term morbidity from DVT is the post-thrombotic syndrome (PTS), which complicates about a quarter of cases of symptomatic proximal DVT; most cases develop within 2 years afterward.
Race

From a demographic viewpoint, Asian and Hispanic populations have a lower risk of VTE, whereas Caucasians and African Americans have a higher risk (2.5-4 times higher).
Sex

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

Deep venous thrombosis (DVT) usually affects individuals older than 40 years.
Clinical
History

* The signs and symptoms of DVT are related to the degree of obstruction to venous outflow and inflammation of the vessel wall. The bedside diagnosis of venous thrombosis is insensitive and inaccurate. Many thrombi do not produce significant obstruction to venous flow; venous collaterals may develop rapidly, and venous wall inflammation may be minimal. Conversely, many nonthrombotic conditions produce signs and symptoms suggestive of DVT. Studies have repeatedly documented this inherent difficulty of the clinical diagnosis of lower extremity DVT.
* Many patients are asymptomatic; however, the history may include the following:
o Edema, principally unilateral, is the most specific symptom. Massive edema with cyanosis and ischemia (phlegmasia cerulea dolens) is rare.
o Leg pain occurs in 50% of patients, but this is entirely nonspecific. Pain can occur on dorsiflexion of the foot (Homans sign).
o Tenderness occurs in 75% of patients but is also found in 50% of patients without objectively confirmed DVT.
o Clinical signs and symptoms of PE as the primary manifestation occur in 10% of patients with confirmed DVT.
o The pain and tenderness associated with DVT does not usually correlate with the size, location, or extent of the thrombus.
o Warmth or erythema of skin can be present over the area of thrombosis.

Physical

No single physical finding or combination of symptoms and signs is sufficiently accurate to establish the diagnosis of DVT. The following is a list outlining the most sensitive and specific physical findings in DVT:

* Edema, principally unilateral
o Tenderness, if present, is usually confined to the calf muscles or along the course of the deep veins in the medial thigh.
o Pain and/or tenderness away from these areas is not consistent with venous thrombosis and usually indicates another diagnosis.
* Homans sign
o Discomfort in the calf muscles on forced dorsiflexion of the foot with the knee straight has been a time-honored sign of DVT. 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.
* Venous distension and prominence of the subcutaneous veins
o 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.
o Patients with superficial thrombophlebitis extending to the saphenofemoral junction are also at higher risk for associated DVT.
o Further diagnostic studies for DVT are required in these particular subgroups of patients.
* Fever: Patients may have a fever, usually low grade. High fever is usually indicative of an infectious process such as cellulitis or lymphangitis.
* Phlegmasia cerulea dolens
o 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.
o 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 or painful blue inflammation. The leg is usually markedly edematous, painful, and cyanotic. Petechiae are often present.
* Phlegmasia alba dolens
o Painful white inflammation was originally used to describe massive ileofemoral venous thrombosis and associated arterial spasm. The affected extremity is often pale with poor or even absent distal pulses.
o The physical findings may suggest acute arterial occlusion, but the presence of swelling, petechiae, and distended superficial veins point to this condition.
* Clinical findings of PE
o These findings are the primary manifestation in about 10% of patients with DVT.
o In patients with angiographically proven PE, DVT is found in 45-70%. In the vast majority of these patients, DVT is clinically silent.

Causes

* The clinical evaluation of patients with suspected DVT is facilitated by an assessment of risk factors. The diagnosis of DVT is confirmed in only 20-30% of ED patients with clinically suspected DVT. The prevalence of DVT in the ED patient population correlates with the number of risk factors present. In patients with no identified risk factors, DVT is confirmed in only 11%. In patients with 3 risk factors, the number rises to 50%.
* The following risk factors for DVT have been identified in many different epidemiologic studies:
o General
+ Age
+ Immobilization longer than 3 days
+ Pregnancy and the postpartum period
+ Major surgery in previous 4 weeks
+ Long plane or car trips (>4 h) in previous 4 weeks
o Medical
+ Cancer
+ Previous DVT
+ Stroke
+ Acute myocardial infarction (AMI)
+ Congestive heart failure (CHF)
+ Sepsis
+ Nephrotic syndrome
+ Ulcerative colitis
o Trauma
+ Multiple trauma
+ CNS/spinal cord injury
+ Burns
+ Lower extremity fractures
o Vasculitis
+ Systemic lupus erythematosus (SLE) and the lupus anticoagulant
+ Behçet syndrome
+ Homocystinuria
o Hematologic
+ Polycythemia rubra vera
+ Thrombocytosis
+ Inherited disorders of coagulation/fibrinolysis
+ Antithrombin III deficiency
+ Protein C deficiency
+ Protein S deficiency
+ Prothrombin 20210A mutation
+ Factor V Leiden
+ Dysfibrinogenemias and disorders of plasminogen activation
o Drugs/medications
+ Intravenous drug abuse
+ Oral contraceptives
+ Estrogens
+ Heparin-induced thrombocytopenia
* The diagnosis of DVT is complicated by the interplay between risk factors, the nonspecific nature of the physical findings, and the frequent discordance between the clinical assessment and the results of objective testing. For example, patients deemed to be at high risk for DVT may have a negative finding on duplex ultrasonographic study. However, the probability of DVT in those patients is still greater than 20%, given the known sensitivity, specificity, and negative likelihood ratio of duplex ultrasonography. Having an objective method to determine pretest probability would simplify clinical management.
* The Wells clinical prediction guide quantifies the pretest probability of DVT. The model enables physicians to reliably stratify their patients into high-, moderate-, 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.

Table 1. Wells Clinical Score for DVT

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Table
Clinical Parameter Score Score
Active cancer (treatment ongoing, or within 6 mo or palliative) +1
Paralysis or recent plaster immobilization of the lower extremities +1
Recently bedridden for >3 d or major surgery <4 wk +1 Localized tenderness along the distribution of the deep venous system +1 Entire leg swelling +1 Calf swelling >3 cm compared with the asymptomatic leg +1
Pitting edema (greater in the symptomatic leg) +1
Previous DVT documented +1
Collateral superficial veins (nonvaricose) +1
Alternative diagnosis (as likely or greater than that of DVT) -2
Total of Above Score
High probability >3
Moderate probability 1 or 2
Low probability ≤ 0
Clinical Parameter Score Score
Active cancer (treatment ongoing, or within 6 mo or palliative) +1
Paralysis or recent plaster immobilization of the lower extremities +1
Recently bedridden for >3 d or major surgery <4 wk +1 Localized tenderness along the distribution of the deep venous system +1 Entire leg swelling +1 Calf swelling >3 cm compared with the asymptomatic leg +1
Pitting edema (greater in the symptomatic leg) +1
Previous DVT documented +1
Collateral superficial veins (nonvaricose) +1
Alternative diagnosis (as likely or greater than that of DVT) -2
Total of Above Score
High probability >3
Moderate probability 1 or 2
Low probability ≤ 0.Differential Diagnoses

Cellulitis
Pulmonary Embolism
Thrombophlebitis, Septic
Thrombophlebitis, Superficial
Other Problems to Be Considered

In approximately 70% of patients with clinically suspected DVT, alternate diagnoses are ultimately found, as follows:

Achilles tendonitis
Arterial insufficiency
Arthritis
Asymmetric peripheral edema secondary to CHF, liver disease, renal failure, or nephrotic syndrome
Cellulitis, lymphangitis
Extrinsic compression of iliac vein secondary to tumor, hematoma, or abscess
Hematoma
Lymphedema
Muscle or soft tissue injury
Neurogenic pain
Postphlebitic syndrome
Prolonged immobilization or limb paralysis
Ruptured Baker cyst
Stress fractures or other bony lesions
Superficial thrombophlebitis
Varicose veins
Workup
Laboratory Studies

D-dimer testing

* The D-dimer test has an important role in the diagnostic approach to deep venous thrombosis (DVT).5,6 D-dimer fibrin fragments are present in fresh fibrin clot and in fibrin degradation products of cross-linked fibrin. Monoclonal antibodies specific for the D-dimer fragment are used to differentiate fibrin-specific clot from non–cross-linked fibrin and from fibrinogen. These specific attributes of the D-dimer antibodies account for their high sensitivity for venous thromboembolism.
* 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. Many of these conditions are associated with higher risk for DVT. The D-dimer assays have low specificity for DVT; therefore, they should only be used to rule out DVT, not to confirm the diagnosis of 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 cut-off value of the assay. This accounts for the reduced sensitivity of the D-dimer assay in the setting of confirmed DVT.
* Many different D-dimer assays are available, with varying sensitivities and specificities. The 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.
* Most studies have confirmed the clinical utility of D-dimer testing, and most clinical algorithms incorporate their use. 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 ED. 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.7
* 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 RBC 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.8
* Current evidence strongly supports the use of a D-dimer assay in the clinical algorithm of suspected DVT.5 A negative D-dimer assay result rules out DVT in patients with low-to-moderate risk (Wells DVT score <2). A negative result also obviates surveillance and serial testing in patients with moderate-to-high risk and negative ultrasonographic findings. * D-dimer results should be used as follows: o A negative D-dimer assay result rules out DVT in patients with low-to-moderate risk and a Wells DVT score less than 2. o 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).

Other blood tests

* Protein S, protein C, antithrombin III, 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.

Imaging Studies

* Because of the inherent inaccuracy of clinical diagnosis that is based on the history, the physical examination, and the assessment of risk factors, D-dimer testing and a determination of pretest probability (eg, Wells DVT score) should be used to identify those patients who require further objective diagnostic testing.
* Diagnosing DVT and committing patients to the risks of anticoagulation therapy without confirmatory objective testing is unacceptable.
* The criterion standard for evaluating patients with suspected DVT has been contrast venography. For many reasons, including allergic reactions, contrast-induced DVT, technical difficulties, inadequate studies, interobserver variability, and lack of availability, venography is either contraindicated or nondiagnostic in as many as 20-25% of patients. As a result, noninvasive studies have essentially replaced venography as the initial diagnostic test of choice.
* Duplex ultrasonography
o Technological advances in ultrasonography have permitted the combination of real-time ultrasonographic imaging with Doppler flow studies (duplex ultrasonography). The major ultrasonographic criterion for detecting venous thrombosis is failure to compress the vascular lumen, presumably because of the presence of occluding thrombus. The absence of the normal phasic Doppler signals arising from the changes to venous flow provides indirect evidence of venous occlusion.
o Many studies have confirmed the diagnostic sensitivity and specificity of duplex ultrasonography for proximal vein thrombosis. Sensitivity of duplex ultrasonography for proximal vein DVT is 97% (95% confidence interval [CI], 96-98%) but only 73% for calf vein DVT (95% CI, 54-93%). The NPV for proximal vein DVT is 99%. Overall specificity is 95%.
o Duplex ultrasonography is also helpful to differentiate venous thrombosis from hematoma, Baker cyst, abscess, and other causes of leg pain and edema.
o The primary disadvantage of duplex ultrasonography is its inherent inaccuracy in the diagnosis of calf vein thrombosis. Venous thrombi proximal to the inguinal ligament are also difficult to visualize. Nonoccluding thrombi may be difficult to detect. In patients with suspected acute recurrent DVT, duplex ultrasonography may not be able to differentiate between old and new clots. Diagnostic accuracy varies depending on local expertise.
* Impedance plethysmography
o In some countries, impedance plethysmography (IPG) has been the initial noninvasive diagnostic test of choice. Plethysmography is derived from the Greek word meaning "to increase." This procedure is based on recording changes in blood volume of an extremity, which are directly related to venous outflow. Several different techniques can be used to measure these changes, including electrical impedance. In the setting of proximal vein thrombosis, venous outflow from the lower extremity is slowed and the blood volume or venous capacitance is increased. Standardized graphs are used to discriminate normal IPG study results from abnormal results.
o In many studies, IPG has been shown to be sensitive and specific for proximal vein thrombosis. It is insensitive for calf vein thrombosis, nonoccluding proximal vein thrombus, and ileofemoral vein thrombosis above the inguinal ligament. IPG cannot distinguish between thrombotic occlusion and extravascular compression of the vein. False-positive results occur in the setting of significant CHF and raised central venous pressure as well as in severe arterial insufficiency.
* MRI
o MRI has increasingly been investigated for evaluation of suspected DVT. In limited studies, the accuracy approaches that of the criterion standard, contrast venography.
o MRI is the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis when CT venography is contraindicated or technically inadequate.
o In the second and third trimester of pregnancy, MRI is more accurate than duplex ultrasonography because the gravid uterus alters Doppler venous flow characteristics.
o In suspected calf vein thrombosis, MRI is more sensitive than any other noninvasive study.
o Expense, lack of general availability, and technical issues limit its use.
* Nuclear medicine imaging studies
o Nuclear medicine studies with I125 -labeled fibrinogen are no longer recommended for patients in the ED. They are relatively insensitive for proximal vein thrombosis and take longer than 24 hours to obtain results. I125 -labeled fibrinogen is no longer available in the United States.
* CT venography

CT venography showing bilateral deep venous throm...
CT venography showing bilateral deep venous thrombosis. Arrows indicate bilateral deep venous thrombosis.

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CT venography showing bilateral deep venous throm...

CT venography showing bilateral deep venous thrombosis. Arrows indicate bilateral deep venous thrombosis.

o With the introduction of multidetector CT technology, CT venography has been incorporated into CT angiographic studies of the chest as part of the diagnostic evaluation for suspected PE. CT venography of the lower extremities is performed after scanning of the chest has been completed. Scanning usually begins at the level of the iliac crests and continues caudally down to the popliteal fossa.
o In the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study reported by Stein et al, the addition of CT venography to CT angiography of the chest increased the diagnostic sensitivity for venous thromboembolic disease than CT angiography alone.9
o A number of small studies have compared CT venography alone to duplex ultrasonography alone for the diagnosis of lower extremity DVT. Similar high sensitivities for ultrasonography and CT have been reported, but no large trials comparing the two have yet been performed.
o The primary utility of CT venography is for the diagnosis of ileofemoral DVT. Ultrasonography is limited to the diagnosis of DVT in the venous system distal to the inguinal ligament. The iliac veins cannot usually be visualized by ultrasonography, and a different diagnostic modality must be used. Herein lies the value of CT venography where venous occlusion proximal to the inguinal ligament may be detected. The diagnosis of ileofemoral DVT should be considered if the ultrasonographic examination reveals thrombus extending into the superficial femoral vein at the inguinal ligament. A CT venogram should be obtained to assess for proximal thrombus and ileofemoral DVT.
o The major problems with CT venography are technical issues with inadequately visualized veins, artifactual interference from metal implants such as hip and knee arthroplasties, and contraindications to the administration of contrast dye.
* Summary - Which test is best?
o When directly compared, duplex ultrasonography has superior sensitivity and specificity over IPG. Guidelines from the American College of Radiology recommend duplex Doppler compression ultrasonography as the most appropriate study in suspected lower extremity DVT. The guidelines note that, in addition to lower accuracy than compression ultrasonography, plethysmography requires meticulous technique and has a sensitivity of only 20-30% for calf vein thrombosis.6
o Controversy still exists over the use of noninvasive studies such as duplex ultrasonography for the diagnosis of suspected calf vein DVT. Recognizing that duplex ultrasonography is relatively insensitive for calf vein thrombosis only matters if the clinician is inclined to place patients with calf vein DVT on anticoagulation therapy. If the clinical algorithm for calf vein thrombosis recommends clinical surveillance and serial studies to detect proximal extension, the lack of sensitivity of the noninvasive study for calf vein thrombosis is irrelevant.
o Reports on the use of noninvasive studies for DVT in asymptomatic hospitalized patients should not be used to determine the optimal evaluation of ED patients with suspected DVT who are usually ambulatory and symptomatic. A number of authors have incorrectly recommended the routine use of contrast venography rather than a noninvasive study for suspected DVT on the basis of the low sensitivity that has been reported in studies of hospitalized patients after hip surgery.
o In ambulatory outpatients with suspected DVT, the sensitivity of duplex ultrasonography for proximal vein thrombosis is 97%, and it remains the initial diagnostic test of choice.
o CT venography is the best diagnostic modality for suspected ileofemoral DVT.
* Simplified clinical management strategy for patients with suspected DVT
o Using the pretest probability score calculated from the Wells DVT score, patients are stratified into 2 risk groups: DVT unlikely (DVT score <2) or DVT likely (DVT score >2).
o Using a sensitive D-dimer assay such as the VIDAS rapid ELISA, the D-dimer results should be used as follows:
+ A negative D-dimer result rules out DVT in the unlikely group (low-to-moderate risk of DVT) with a Wells DVT score less than 2.
+ All patients with a positive D-dimer result and all patients in the likely group (moderate-to-high risk of DVT) with a Wells DVT score of 2 or greater require a diagnostic study (ie, duplex ultrasonography).
* The results from duplex ultrasonography are incorporated as follows:
o If the patient is scored as likely and the duplex ultrasonographic findings are positive, treat for DVT.
o If the duplex study result is negative and the patient is scored as unlikely to have DVT, DVT is ruled out even if the D-dimer assay is positive.
o When discordance exists between the pretest probability and the duplex ultrasonographic study result, further evaluation is required.
o If the patient is scored as likely to have DVT (DVT score >2) but the ultrasonographic findings are negative, the patient still has a significant probability of DVT. Some authors recommend venography to rule out a calf vein DVT that ultrasonography did not detect. Most recommend surveillance with repeat clinical evaluation and ultrasonography in 1 week. Others use the results of the D-dimer assay to guide management. A negative D-dimer assay in combination with negative ultrasonographic findings rules out DVT. A positive D-dimer assay in this group mandates surveillance and repeat ultrasonography in 1 week.
o If the patient is scored as unlikely to have DVT (DVT score <2) but the ultrasonographic findings are positive, some authors recommend a second confirmatory study such as venography before treating for DVT and committing the patient to the risks of anticoagulation. Most, however, treat the patient for DVT. o If the patient is scored as likely to have DVT (DVT score >2) but had a positive D-dimer assay result and the ultrasonographic findings are negative, repeat clinical evaluation and ultrasonography in 1 week is recommended.
* The DVT score was developed in a specific subgroup of patients. Excluded from the model were patients with suspected coexistent PE and patients already taking anticoagulants. Therefore, the evaluation and subsequent treatment of these excluded subgroups must be individualized.

Other Tests
Mahmoodi et al found that microalbuminuria is independently associated with an increased risk for venous thromboembolism (VTE). In a community-based prospective cohort study of 8574 subjects, the risk of VTE rose in tandem with the rate of urinary albumin excretion: the annual incidence of VTE was 0.12% among participants with <15 mg albumin per 24-hour urine collection compared with 0.40% among those with 30-300 mg albumin per 24 hours. Adjusted hazard ratio for microalbuminuria versus normoalbuminuria (ie, <30 mg/24 h) was 2.00 (P <0.001).Treatment Emergency Department Care 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 postphlebitic syndrome. The current guidelines recommend short-term anticoagulation with LMWH SC (Grade 1A), unfractionated heparin IV (Grade 1A), fixed-dose unfractionated heparin SC (Grade 1A), or fondaparinux SC (Grade 1A). Initial treatment with LMWH, unfractionated heparin, or fondaparinux should continue for at least 5 days and until the INR is >2 for 24 hours (Grade 1C). A vitamin K antagonist such as warfarin should be initiated together with LMWH, unfractionated heparin, or fondaparinux on the first treatment day (Grade 1A).11

Anticoagulation

Heparin

Anticoagulation remains the mainstay of the initial treatment for DVT. Regular unfractionated heparin was the standard of care until the introduction of low-molecular-weight-heparin (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 emboli as well as recurrent thrombosis. The primary reason for the persistent, albeit reduced, risk of PE is primarily due to the fact that heparin has no effect on preexisting nonadherent thrombus. Heparin does not affect the size of existing thrombus and has no intrinsic thrombolytic activity.

Heparin therapy is associated with complete lysis in fewer than 10% of patients studied with venography after treatment.

Heparin therapy has little effect on the risk of developing the postphlebitic syndrome. The original thrombus causes venous valvular incompetence and altered venous return leading to a high incidence of chronic venous insufficiency and postphlebitic syndrome.

The anticoagulant effect of heparin is directly related to its activation of antithrombin III. Antithrombin III, the body's primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process.

Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity. The larger fragments primarily interact with antithrombin III to inhibit thrombin. 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.

Warfarin therapy is overlapped with heparin for 4-5 days until the international normalized ratio (INR) is therapeutically elevated to 2-3. Heparin must be overlapped with oral warfarin because of the initial transient hypercoagulable state induced by warfarin. This effect is related to the differential half-lives of protein C, protein S, and the vitamin K–dependent clotting factors II, VII, IX, and X. Long-term anticoagulation is definitely indicated for patients with recurrent venous thrombosis and/or persistent or irreversible risk factors.

When intravenous unfractionated heparin is initiated for DVT, the goal is to achieve and maintain an elevated activated partial thromboplastin time (aPTT) of at least 1.5 times control. Heparin pharmacokinetics are complex; the half-life is 60-90 minutes. A protocol for IV heparin use is as follows:

1. Give an initial bolus of 80 U/kg
2. Initiate a constant maintenance infusion of 18 U/kg.
3. Check the aPTT or Heparin Activity level 6 hours after the bolus and adjust the infusion rate accordingly.
4. Continue to check the aPTT or heparin Activity level every 6 hours until 2 successive values are therapeutic.
5. Monitor the aPTT or Heparin Activity level, hematocrit, and platelet count every 24 hours.

Heparin-induced thrombocytopenia is not infrequent. In this condition, platelet aggregation induced by heparin may trigger venous or arterial thrombosis with significant morbidity and mortality. Unfortunately, it is not possible to predict which subset of patients will develop thrombosis. All patients who develop thrombocytopenia while taking heparin are at risk. Alternatives include the substitution of porcine for bovine heparin, the use of LMWH, or initiation of therapy with warfarin alone.

Traditionally, heparin has been used only for admitted patients with DVT. In a recent study by Kearon et al, fixed-dose subcutaneous unfractionated heparin was evaluated for outpatient treatment of DVT.12 In this randomized, primarily outpatient, open-label, adjudicator-blinded, noninferiority trial of 708 adult patients with objectively confirmed DVT fixed-dose subcutaneous unfractionated heparin (UFH) was compared to LMWH (enoxaparin or dalteparin). In the UFH group, 333 units/kg of unfractionated heparin was administered subcutaneously initially followed by a fixed dose of 250 units/kg twice daily. This was overlapped with oral warfarin for 5 days until the INR was considered therapeutic. In the LMWH group, 100 IU/kg of the LMWH was administered twice daily.

Recurrent venous thromboembolism (VTE) occurred in 13 patients in the UFH group (3.8%) compared with 12 patients in the LMWH group (3.4%; absolute difference 0.4%; 95% CI, -2.6% - 3.3%). Major bleeding during the first 10 days of treatment occurred in 1.1% of the UFH group versus 1.4% in the LMWH group (absolute difference -0.3%; 95% CI, -2.3% - 1.7%) The authors concluded that fixed-dose UFH is as safe and effective as LMWH in patients with acute DVT and is suitable for outpatient treatment.

Low-Molecular-Weight Heparin

LMWH is prepared by selectively treating unfractionated heparin to isolate the low-molecular-weight (<9,000 Da) fragments. Its activity is measured in units of factor X inactivation, and monitoring of the aPTT is not required. The dose is weight adjusted. LMWH products are administered subcutaneously, and their half-life permits single- or twice-daily dosing. Its use in the outpatient treatment of DVT and PE has been evaluated in a number of studies. At the present time, 4 LMWH preparations, enoxaparin, dalteparin, tinzaparin, and nadroparin, are available. Enoxaparin, dalteparin, and tinzaparin have received US Food and Drug Administration (FDA) approval for the treatment of DVT in the United States. Enoxaparin is approved for inpatient and outpatient treatment of DVT. Nadroparin is approved for DVT treatment in Canada. The increased bioavailability and prolonged half-life of LMWH allows for outpatient treatment of DVT using once - or twice-daily subcutaneous treatment regimens. Outpatient treatment of acute DVT with LMWH has been successfully evaluated in a number of studies and is currently the treatment of choice if the patient is eligible. In general, outpatient management is not recommended if the patient has proven or suspected concomitant PE, significant comorbidities, extensive ileofemoral DVT, morbid obesity, renal failure, or poor follow-up (see exclusion criteria for outpatient management). The efficacy and safety of LMWH for the initial treatment of DVT have been well established in several trials. Mismetti and colleagues13 have conducted a systematic meta-analysis of the original source data to specifically address the question whether the efficacy and safety of enoxaparin, a LMWH, is modified by the presence or absence of initial PE at baseline. PE is recognized as a sequela of DVT, and most cases of PE are recognized to arise from DVT of the lower extremities. Previous meta-analyses of published trials could not evaluate the efficacy and safety of LMWH if PE was present in addition to DVT because they reviewed only published summarized data. The authors reanalyzed the original individual source data from 1503 patients in 3 randomized controlled trials. Efficacy was assessed through objectively confirmed recurrence of DVT and/or PE. The authors also used a well-established margin of noninferiority for the treatment effect that was calculated prior to data collection. Enoxaparin 1 mg/kg twice daily was found to be noninferior to UFH in the treatment of DVT with or without a coexisting PE.Inaddition, while not statistically significant, a trend favoring enoxaparin over UFH was also observed in the incidence of major bleeding and all-cause mortality at 3 months. Although LMWH is noninferior to UFH in the treatment of DVT, the emergency physician must recognize that, despite adequate anticoagulant therapy, the recurrence rate for DVT and/or PE when enoxaparin was used was still 4.5%. With UFH, the recurrence rate for DVT, PE, or both was 4.4%, 1.8%, and 5.7%, respectively. The incidence of DVT and PE recurrence in patients presenting with DVT and an initial symptomatic PE is much higher, approaching 8.2% in the UFH group compared with 4.8% in patients with DVT alone. When comparing the efficacy of enoxaparin versus UFH, no significant difference between patients with and without an initial symptomatic PE was noted. However, the risk of recurrent PE was also higher in patients with an initial symptomatic PE despite adequate anticoagulant therapy. Therefore, a recurrent VTE event must be considered in patients who present to the emergency department with recurrent symptoms despite adequate anticoagulant therapy. Incidentally, the group of patients presenting withDVTand symptomatic PE were found more often to be women with a previous history of VTE, and thus, inherently at greater risk for VTE recurrence. A Canadian study by Wells et al compared tinzaparin with dalteparin, the former being the only LMWH to have demonstrated statistical superiority to UFH in the prevention of DVT recurrence. Wells et al conducted this single-blind, randomized controlled trial of 505 outpatients with objectively proven DVT. In addition to subcutaneous LMWH, patients were simultaneously begun on warfarin using a standardized normogram. After 5 days and an INR of 2 or greater, the LMWH was stopped and oral anticoagulation was continued for 3 months. A composite end-point, combining both the risk of recurrent thrombosis or PE and the risk of hemorrhage, was used as the most appropriate assessment of the two pharmacotherapies.14 The existing literature had predicted outcomes in favor of tinzaparin by a minimal but clinically important 4% combined end-point. However, with combined event rates of 4.8% and 5.4% for dalteparin and tinzaparin, respectively, tinzaparin was not found to be superior to dalteparin, andboththerapies provided safe and efficacious outpatient treatment of acute DVT and PE. However, in December 2008, the FDA issued a communication that recommended considering alternatives to tinzaparin for treatment of DVT in patients older than 70 years with renal insufficiency, because of increased risk of death in that population.15 The study by Wells et al14 was the first trial to compare drugs within the LMWH class, and it also was the first study to treat patients with acute DVT and PE solely on an outpatient basis. The question of whether there is any significant clinical difference between these LMWH agents for the treatment of DVT or PE was only partially answered. The authors estimated that the projected sample size needed to detect any significant difference between dalteparin and tinzaparin would exceed 30,000 patients. Such a study is unlikely to be funded at the present time. Once-Daily Versus Twice-Daily Enoxaparin Van Dongen and colleagues16 as part of the Cochrane Database of Systemic Reviews performed a meta-analysis to specifically evaluate the safety and efficacy of once-daily versus twice-daily dosing of enoxaparin for treatment of DVT. The authors hypothesized that twice-daily dosing would be more effective and safer with fewer bleeding complications. Higher frequency of dosing would allow more stability in anticoagulation; therefore, they expected fewer complications with this group. Using strict criteria for exclusion, they compared 5 randomized controlled trials with a total of 1508 patients. These trials all involved patients treated for initial VTE. When the data was pooled, the actual incidence of VTE recurrence between the two groups was not statistically significant, complying with the predetermined equivalence criteria. In assessing discrepancies in thrombus size, no statistical difference was noted. A lower mortality was observed in the twice-daily group, while a lowerincidence ofhemorrhage was seen in the once-daily group, but again, neither of these differences was statistically significant. While admitting that the wide confidence interval led to decreased precision in these results, the authors concluded that once-daily dosing is as safe and efficacious as the standard twice-daily regimen. Enoxaparin in the Morbidly Obese, in Renal Failure, in Pregnancy, and in Cancer A number of questions have arisen about the use of enoxaparin in special patient populations such as those with renal insufficiency, those who are pregnant, and those who are morbidly obese. The article by Michota reviewed the efficacy, safety, and dosing of enoxaparin in DVT prophylaxis and in the treatment of VTE in special patient populations—the morbidly obese, pregnancy, renal insufficiency, and cancer. Given the prevalence of obesity, a problem that afflicts one third of Americans today, Michota reviewed its effect on enoxaparin dosing. Morbid obesity was defined as body weight greater than 150 kg or a BMI greater than 50.17 The author noted that there is a paucity of morbidly obese patients represented in the major clinical trials evaluating the LMWH agents. The authors cited a British trial that demonstrated decreased anti-Xa activity with increased body weight when fixed as opposed to weight-based enoxaparin dosing was used. The relationship between intravascular volume, volume of distribution of the drug, and body weight is not linear. Therefore, there is concern that weight-based dosing in the morbidly obese patient population might lead to an excessive rate of bleeding complications. However, other studies have shown that no significant increase in anti-Xa activity occurs when weight-based dosing of LMWH is used. In a cardiovascular trial, no increase in bleeding rates between obeseandnonobese patients was documented when full weight-based dosing was used. In morbidly obese patients, the author concluded that, although the general consensus suggests that weight-based dosing without a cap is currently recommended, a paucity of data supports it. Therefore, the author concluded that it is not unreasonable to initiate therapy with full weight-based dosing and to monitor the anti-Xa levels.17 The therapeutic ranges for anti-Xa activity for the various LMWH compounds are listed in Table 2 (below). Anti-Xa levels are drawn 4 hours after a subcutaneous dose. Enoxaparin dosing has also been poorly studied in patients with renal conditions. Higher peak anti-Xa levels as well as half-life prolongation correlate with decreasing creatinine clearance because LMWH is renally cleared. Patients with renal failure may be at increased risk for bleeding secondary to excessive anticoagulation. Several trials have substantiated increased bleeding rates with UFH and LMWH among patients with renal insufficiency (CrCl <30mL/min). Although UFH has a dual clearance mechanism and is less susceptible to drug accumulation in renal insufficiency than LMWH, its greater adverse effect on platelet function and capillary permeability leads to a similar rate of bleeding problems. A negative linear correlation exists between anti-Xa activity and CrCl. As a result, the FDA issued new dosing guidelines for enoxaparin of 1 mg/kg daily instead of twice a day. No revised dosing guidelines are available for the other LMWH agents. Michota also concluded that monitoring of anti-Xa levelsisthe safest approach in patients with chronic renal insufficiency.17 In pregnant patients with VTE, LMWH has clear advantages over UFH including better bioavailability, lower incidence of heparin-induced thrombocytopenia and osteoporosis, and reduced monitoring requirements. Throughout pregnancy, the volume of distribution of LMWH is larger. Drug clearance is higher in early pregnancy and trends toward normal at delivery. Therefore, monitoring of anti-Xa levels is important. Drug therapy should be initiated at the same dose as for nonpregnant patients, but the dose may have to be increased if anti-Xa levels fall below the therapeutic ranges outlined in Table 2. Therapy should be held during delivery but then restarted postpartum and continued while the patient is crossed over to a vitamin K antagonist. Table 2. Therapeutic Peak Anti-Xa levels With Low-Molecular-Weight Heparins for Treatment of Venous Thromboembolism Open table in new window [ CLOSE WINDOW ] Table Low-Molecular-Weight Heparin Therapeutic Peak Enoxaparin 1 mg/kg q12h hours 0.6-1 IU/mL Enoxaparin 1.5 mg/kg daily 1-1.5 IU/mL Tinzaparin 175 IU/kg daily 0.85-1 IU/mL Dalteparin 100 IU/kg q12h hours 0.4-1.1 IU/mL Dalteparin 200 IU/kg daily 1-2 IU/mL Low-Molecular-Weight Heparin Therapeutic Peak Enoxaparin 1 mg/kg q12h hours 0.6-1 IU/mL Enoxaparin 1.5 mg/kg daily 1-1.5 IU/mL Tinzaparin 175 IU/kg daily 0.85-1 IU/mL Dalteparin 100 IU/kg q12h hours 0.4-1.1 IU/mL Dalteparin 200 IU/kg daily 1-2 IU/mL *VIa chromogenic: Anti-Xa assay drawn 4 hours after subcutaneous dose. Patients with cancer have a particularly higher rate of DVT recurrence than noncancer patients. Long-term therapy for DVT is strongly recommended. Recent studies have shown a lower rate of VTE recurrence without increasing the risk of bleeding with 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 (Coumadin) if the patient's insurance will cover it.17 Fondaparinux, a Direct Factor Xa Inhibitor in Acute DVT Currently, enoxaparin and other LMWH agents are recommended for the treatment of DVT. However, the data on once-daily or twice-daily dosing of enoxaparin is not clear. Secondly, the practical issues that surround the administration of a weight-based 1 mg/kg dose from fixed-volume syringes of enoxaparin may be an issue for some patients. Thirdly, the incidence of heparin-induced thrombocytopenia, although reduced with enoxaparin, is not completely eliminated. Fondaparinux, a direct selective inhibitor of factor Xa, overcomes many of these disadvantages. 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 has not been reported. Therapeutic monitoring of laboratory parameters such as the prothrombin time orpartialthromboplastin time is also not required. Buller and his coauthors on behalf of the Matisse Investigators conducted a randomized double-blind international study of fondaparinux versus enoxaparin on 2205 patients with objectively confirmed acute DVT.11 The efficacy and safety of fondaparinux was compared with enoxaparin. 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 vitamin K antagonist until a therapeutic INR was achieved. Anticoagulation with a vitamin K antagonist 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. 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%). 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.11 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.18 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. Isolated Calf Vein DVT Despite the lower (but not zero) risk of PE and mortality associated with calf vein DVT, current guidelines recommend short-term anticoagulation for 3 months in symptomatic patients albeit with a relatively low Grade 2B recommendation. Asymptomatic patients with isolated calf vein DVT do not require anticoagulation, and surveillance ultrasound studies over 10-14 days to detect proximal extension is recommended instead.11 Thrombolytic Therapy for DVT Thrombolytic therapy offers significant advantages over conventional anticoagulant therapy including the prompt resolution of symptoms, the prevention of PE, the restoration of normal venous circulation, the preservation of venous valvular function, and the prevention of postphlebitic syndrome. Thrombolytic therapy does not prevent clot propagation, rethrombosis, or subsequent embolization. Heparin therapy and oral anticoagulant therapy must always follow a course of thrombolysis. Unfortunately, most patients with DVT have absolute contraindications to thrombolytic therapy. Thrombolytic therapy is also not effective once the thrombus is adherent and begins to organize. Venous thrombi in the legs are often large and associated with complete venous occlusion. The thrombolytic agent that acts on the surface of the clot may not be able to penetrate and lyse the entire thrombus. Nevertheless, the data from many published studies indicate that thrombolytic therapy is more effective than heparin in achieving vein patency. The unproven assumption is that the degree of lysis observed on posttreatment venography is predictive of future venous valvular insufficiency and late (5-10 y) development of postphlebitic syndrome. Preliminary evidence suggests that thrombolytic therapy reduces but unfortunately does not entirely eliminate the incidence of postphlebitic syndrome at 3 years. The hemorrhagic complications of thrombolytic therapy are formidable (~3 times higher) and include the small but potentially fatal risk of intracerebral hemorrhage. The uncertainty regarding thrombolytic therapy is likely to continue. Currently, 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. Catheter-directed intrathrombus thrombolysis (CDT) is an image-guided therapy where a thrombolytic agent is administered directly into the thrombus and enhances thrombus removal. A variety of specialized catheters and mechanical devices are used to optimally deliver the drug and mechanically remove the clot. Secondly, balloon angioplasty and stents may be used at the same time to treat any underlying venous obstruction that predisposes the patient to recurrent DVT. Direct intrathrombus delivery of the thrombolytic agent achieves higher drug concentration at the site of thrombosis with a lower total dose than would be used by systemic intravenous thrombolytic therapy. This is the suggested mechanism for the lower incidence of systemic and in particular intracranial hemorrhagic complications with CDT. The Society of Interventional Radiology (SIR) has published a position paper that supports the adjunctive use of CDT in addition to anticoagulant therapy for carefully selected patients with acute ileofemoral deep vein thrombosis. The authors evaluated this therapeutic option in the context of the major therapeutic goals for the treatment of DVT: (1) provision of early symptom relief, (2) prevention of the postthrombotic syndrome (PTS), and (3) prevention of PE.19 The authors of the position statement cited a number of comparative studies that support the use of CDT to prevent PTS and provide rapid symptom relief. They explained that the natural history of ileofemoral vein DVT is different than isolated femoral-popliteal DVT. In the latter group, recanalization and collateral venous blood flow limit the degree of PTS. However, in the iliac veins, adequate recanalization is unlikely and collateral venous blood flow is minimal. This leads to persistent venous outflow obstruction and an increased risk of PTS. Long-term studies of patients with ileofemoral DVT reported a 44% incidence of venous claudication at 5-year follow-up with standard anticoagulant therapy alone. Furthermore, the rate of recurrence of DVT is twice as high in patients with an ileofemoral DVT than in those with more distal, femoral-popliteal DVT. The authors referenced a meta-analysis that demonstrated a 90% success rate with CDT for thrombus removal as well as a case-control study that reportedadecreased incidence of PTS compared with anticoagulant therapy alone. SIR recognized that the main risk of adjunctive CDT is bleeding. Their pooled review of 19 published studies reported an 8% incidence of major bleeding (mostly at the catheter insertion site) and an intracranial bleeding rate of only 0.2%, which is less than that reported for systemic thrombolytic therapy. However, the range of major bleeding risk in the studies reviewed was actually 0-24%. The incidence of PE was 1%, which is also less than the incidence of PE complicating standard anticoagulant therapy. However, they conceded that no prospective randomized study has yet been conducted to evaluate CDT compared with standard anticoagulant therapy for ileofemoral DVT. In conclusion, the SIR affirmed that the available evidence defended a clinical benefit of CDT in the specific subgroup of patients with ileofemoral DVT, limb-threatening disease, and low bleeding risk.19 The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial has just started to determine if a noninvasive approach with CDT and a thrombus removal device is superior to standard noninvasive anticoagulant therapy in preventing or reducing the incidence of the post-thrombotic syndrome in patients with proximal DVT including ileofemoral DVT. For the practicing emergency physician, considering the diagnosis of ileofemoral DVT, obtaining the appropriate imaging study (CT venography), recognizing the indications for CDT, and consulting an interventional radiologist or vascular surgeon when necessary is more important. Filters for DVT The idea of placing a barrier in the inferior vena cava to prevent PE from DVT was first suggested by Trousseau in 1868. In the mid 1900s before the adoption of anticoagulant therapy, DVT and PE were generally managed by laparotomy and vena caval ligation. Mortality rates were high. The next evolutionary step was the introduction of vena caval clips that were applied during laparotomy. These were meant to decrease the luminal diameter of the IVC but were also associated with poor results. The concept of inferior vena cava filters arose from the recognition of these late complications of surgical ligation of the inferior vena cava as first proposed by Homans in 1934. These permanent filters were inserted transvenously under simple local anesthesia. The current benchmark standard is the Greenfield filter. More than 20 years of long-term follow-up experience with this filter is available. Its design incorporates all the features of an ideal filter—maintain caval patency, trap emboli, preserveprogradecaval blood flow, avoid stasis, and enhance thrombolysis of trapped emboli. The Greenfield filter achieves a long-term patency rate of 98% with only a 4% incidence of recurrent PE. Generally accepted indications for filter placement are (1) severe hemorrhagic complications on anticoagulant therapy or other absolute contraindications to anticoagulation and (2) failure of anticoagulant therapy, such as new or recurrent venous thrombosis or PE, despite adequate anticoagulation. Surprisingly, only one randomized controlled study on venocaval filters has been performed. The study was by Decousus et al and was published in 1998. This trial randomized 400 patients with proximal DVT to filter or no filter groups. Both groups were anticoagulated with UFH. This study design excluded patients with contraindications to anticoagulation, which is one of the major indications for a veno-caval filter. After 12 days, a statistically significant reduction occurred in PE in the filter group (1.1% vs 4.8%, P= 0.03), but this disappeared at 2 years to become 3.4% versus 6.3%, P= 0.16. Significantly, the incidence of later DVT was much higher in the filter group (21% vs 12%, P=0.02).20 The Decousus study propelled the development and introduction of temporary/optionally retrievable filters that provide temporary prophylaxis for PE yet avoid the longer-term risk of later DVT. Unfortunately, randomized prospective studies evaluating the use of these retrievable filters, despite their ever-increasing use, are lacking. Today, more than 10 different retrievable vena cava filters are available. This begs the question: who gets what filter? Rectenwald in his review article points out that, despite the fact that these new filters are supposed to be removed or repositioned within 2-6 weeks, less than 50% are actually removed.21 This review questions the rationale for placing a temporary filter for permanent use without long-term studies when more than 20 years of experience is available with the permanent Greenfield filter. The major indications for vena caval filters are primarily for patients with a contraindication to anticoagulation or for patients with major complications while anticoagulated (hemorrhage or heparin-induced thrombocytopenia). The use of vena caval filters has expanded to include primary venous thromboembolism (VTE) prophylaxis in special patient populations such as major trauma patients, major surgery patients, advanced malignancy, and neurological or neurosurgical patients with paralysis or prolonged immobilization. These special patient populations are generally characterized by contraindications to anticoagulation, ineffective anticoagulant prophylaxis, hypercoagulable states, or other exceedingly high risks of PE. Currently, the newer filters are placed under ultrasonographic guidance either by transabdominal or by intravascular ultrasonography. The advantage of ultrasonography is that the filters may be placed at the bedside in the ICU or the ED, thereby avoiding the pitfalls and difficulties of transporting the patient to the angiography suite. Transabdominal ultrasonography machines are generally more readily available, do not require a separate femoral venous puncture, and there is more experience with their use. However, the patient's body habitus must provide adequate acoustic windows to permit the transabdominal technique. There is a need for more study and more data on which filter to use. The temporary optionally retrievable filters have the ultimate advantage but currently are removed less than half the time and no proven long-term results are available. Surgery for DVT Surgical therapy for DVT may be indicated when anticoagulant therapy is ineffective, unsafe, or contraindicated. The major surgical procedures for DVT are clot removal and partial interruption of the inferior vena cava to prevent PE. The rationale for thrombectomy is to restore venous patency and valvular function. Thrombectomy alone is not indicated because rethrombosis is frequent. Heparin therapy is a necessary adjunct. Thrombectomy is reserved for patients with massive ileofemoral vein thrombosis (phlegmasia cerulea dolens) with vascular compromise when thrombolysis is absolutely contraindicated. Compression stockings (routinely recommended) The postthrombotic syndrome affects approximately 50% of patients with DVT after 2 years. Elderly patients and patients with recurrent ipsilateral DVT have the highest risk. Below-the-knee elastic stockings assist the calf muscle pump and reduce venous hypertension and venous valvular reflux. This reduces leg edema, aids the microcirculation, and prevents venous ischemia. Prandoni and colleagues conducted a randomized controlled study in an Italian university setting involving 180 patients who presented with a first episode of symptomatic proximal DVT. They sought to evaluate the efficacy of graduated below-the-knee elastic compression stockings (ECS) in the prevention of the postthrombotic syndrome (PTS). After conventional anticoagulation with heparin, patients were discharged on therapeutic warfarin for 3-6 months and randomly assigned to the control (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.22 A standardized validated scale was used to assess symptoms, severity, and/or progression of PTS. The postthrombotic syndrome 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=0.011) in favor of ECS.22 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 the syndrome 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 symptomaticproximalDVT to prevent the development of the 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. With the adoption of outpatient therapy for proximal DVT, the initial management of DVT increasingly becomes the responsibility of the emergency physician. It therefore behooves us to prescribe graduated elastic compression stockings to all our DVT patients at discharge. Ambulation Controversy exists regarding the role of ambulation in the therapy of DVT. The study by Partsch reviews the myths surrounding immediate ambulation and compression in the patient with newly diagnosed DVT. 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 PTS. The authors cite 2 small previous studies that demonstrated that the incidence of a new PE after initiation of anticoagulant therapy with a 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 thatonly77 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. The authors concluded that early ambulation and compression is not associated with any significant risk of PE.23 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.24 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 VTE also recommends ambulation as tolerated for patients with DVT. Therefore, early ambulation on day 2 after initiation of outpatient anticoagulant therapy in addition to effective compression is strongly recommended. Early ambulation without compression stockings is not recommended. The fear of dislodging clots and precipitating a fatal PE is unfounded. Consultations * Hematologist * Vascular surgeon * Radiologist * Interventional radiologist Medication The goals of pharmacotherapy in venous thrombosis are to reduce morbidity, to prevent the postphlebitic syndrome, and to prevent PE, all with minimal adverse effects and cost. Anticoagulants These agents prevent recurrent or ongoing thrombolytic occlusion of the vertebrobasilar circulation. Fondaparinux sodium (Arixtra) Synthetic anticoagulant, which works by inhibiting factor Xa, a key component involved in blood clotting. Provides highly predictable response. Bioavailability is 100%, has a rapid onset of action, and a half-life of 14-16 h, allowing for sustained antithrombotic activity over 24-h period. Does not affect PT or aPTT, and it does not affect platelet function or aggregation. Prevent DVT, which may lead to PE, in patients undergoing orthopedic surgery who are at risk for thromboembolic complications. * Dosing * Interactions * Contraindications * Precautions Adult Prophylaxis: 2.5 mg SC qd starting 6 h after surgery for 5-11 d; may administer up to 24 additional days following hip fracture Treatment: <50 kg: 5 mg SC qd 50-100 kg: 7.5 mg SC qd >100 kg: 10 mg SC qd
Initiate warfarin within 72 h and continue fondaparinux for at least 5 d until oral anticoagulant effect established (ie, INR 2-3)
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

None reported; increased risk of bleeding possible with concurrent administration of platelet inhibitors, oral anticoagulants, or thrombolytic agents

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; seriously impaired kidney function or in patients who weigh <110 lb; patients given spinal anesthesia or spinal puncture * Dosing * Interactions * Contraindications * Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions When spinal anesthesia or spinal puncture used, may develop blood clot in spine, which can result in long-term or permanent paralysis (holding 2 doses prior to LP or surgery is recommended); major bleeding risk increased when initiated before 6 h following surgery; elimination decreased in elderly patients and in those with renal impairment Heparin Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of a clot after a spontaneous fibrinolysis. * Dosing * Interactions * Contraindications * Precautions Adult 80 U/kg IV bolus, followed by 18 U/kg/h maintenance infusion Monitor aPTT or heparin activity level and titrate infusion rate accordingly Pediatric Administer as in adults * Dosing * Interactions * Contraindications * Precautions Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; subacute bacterial endocarditis; severe liver disease; hemophilia; active bleeding; history of heparin-induced thrombocytopenia * Dosing * Interactions * Contraindications * Precautions Pregnancy A - Fetal risk not revealed in controlled studies in humans Precautions In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock Dalteparin (Fragmin) Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Except in overdoses, no utility exists in checking PT or aPTT because aPTT does not correlate with anticoagulant effect of fractionated LMWH. Average duration of treatment is 7-14 d. * Dosing * Interactions * Contraindications * Precautions Adult Abdominal surgery: 2500 IU SC qd for 5-10 d High-risk patients undergoing abdominal surgery: 5000 IU SC qd for 5-10 d Hip arthroplasty: 2500 IU SC 4-8 h following surgery, then 5000 IU SC qd for up to 14 d Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; major bleeding, thrombocytopenia; regional anesthesia * Dosing * Interactions * Contraindications * Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminase levels may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; protamine sulfate will reverse effect if significant bleeding complications develop; cases of epidural/spinal hematomas have been reported in adults receiving spinal or epidural anesthesia (holding 2 doses prior to LP or surgery is recommended); when using for extended treatment in patients with cancer, if platelet count decreases <100,000/mm3, reduce dose by 2500 IU until platelet count recovers, and discontinue if platelet count <50,000/mm3 (may resume previous dose when platelets recover); reduce dose with impaired renal function (monitor anti-Xa levels) Warfarin (Coumadin) Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders. Dose must be individualized and adjusted to maintain INR at 2-3. * Dosing * Interactions * Contraindications * Precautions Adult 2-10 mg/d PO Pediatric Weight-based dose of 0.05-0.34 mg/kg/d PO; adjust according to desired INR Infants may require doses at or near high end of this range * Dosing * Interactions * Contraindications * Precautions Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate Medications that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; severe liver or kidney disease; risk of CNS hemorrhage; cerebral aneurysms; open wounds or bleeding of the GI, GU, or respiratory tract * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes mellitus; patients with protein C or S deficiency are at risk of skin necrosis Enoxaparin (Lovenox) LMWH used in treatment of DVT and PE as well as DVT prophylaxis. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. Slightly affects thrombin and clotting time and preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d. * Dosing * Interactions * Contraindications * Precautions Adult 1 mg/kg SC bid; alternatively, administer 1.5 mg/kg SC qd Pediatric Not established The following doses have been suggested: <2 months: 0.75 mg/kg/dose SC bid >2 months: 0.5 mg/kg/dose SC bid

* Dosing
* Interactions
* Contraindications
* Precautions

Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; major bleeding; history of heparin-induced thrombocytopenia

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminase levels may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop

Tinzaparin (Innohep)

Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.
Average duration of treatment is 7-14 d.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

175 U/kg SC qd, at same time each day, for >6 d and until patient is adequately anticoagulated with warfarin (INR >2 for 2 consecutive days)
Pediatric

Not established; adult dose suggested

* Dosing
* Interactions
* Contraindications
* Precautions

Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; major bleeding; heparin-induced thrombocytopenia (current or history of)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

The FDA has recommended considering alternatives to tinzaparin for treatment of DVT in patients over 70 years of age with renal insufficiency, because of increased risk of death. If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminase levels may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; 1 mg of protamine sulfate reverses the effect of approximately 100 U of tinzaparin if significant bleeding complications develop
Thrombolytics

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.

Tenecteplase (TKNase)

Modified version of alteplase (tPA) made by substituting 3 amino acids of alteplase. Has longer half-life and, thus, can be given as single bolus over 5 sec infusion instead of 90 min with alteplase. Appears to cause less non-intracranial bleeding but has similar risk of intracranial bleeding and stroke as alteplase. Base the dose using patient weight. Initiate treatment as soon as possible after onset of AMI symptoms. Because tenecteplase contains no antibacterial preservatives, reconstitute immediately before use.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Give IV bolus over 5 sec using body weight, not to exceed 50 mg
<60 kg: 30 mg (6 mL) 60-70 kg: 35 mg (7 mL) 70-80 kg: 40 mg (8 mL) 80-90 kg: 45 mg (9 mL) >90 kg: 50 mg (10 mL)
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Heparin and vitamin K antagonists, acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors may increase risk of bleeding if coadministered with tenecteplase therapy

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active internal bleeding; intracranial neoplasm, arteriovenous malformation, or aneurysm; history of cerebrovascular accident; intracranial or intraspinal surgery or trauma within 2 mo; known bleeding diathesis; severe uncontrolled hypertension

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution if readministering to patients who have received prior plasminogen activator therapy (may develop immunity); coronary thrombolysis may result in arrhythmias associated with reperfusion but not different from those often seen in ordinary course of acute MI (may be managed with standard antiarrhythmic measures); in elderly patients, weigh benefits of tenecteplase on mortality against risk of increased adverse events, including bleeding; cholesterol embolism is associated with all types of thrombolytic agents, but true incidence is unknown

Urokinase (Abbokinase)

Direct plasminogen activator isolated from human fetal kidney cells grown in culture. Acts on endogenous fibrinolytic system and converts plasminogen to enzyme plasmin. Plasmin degrades fibrin clots, fibrinogen, and other plasma proteins. It is nonantigenic but more expensive than streptokinase, which limits its use. When used for purely local fibrinolysis, it is administered as local infusion directly into area of thrombus and with no bolus.
Adjust dose to achieve clot lysis or patency of affected vessel.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

4400 U/kg IV bolus followed by maintenance infusion at 4400 U/kg/h for 1-3 d
For regional thrombus-directed therapy, smaller bolus of 250,000 U IV may be given followed by infusion at 500-2000 U/kg/h
Pediatric

Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; internal bleeding; recent trauma including cardiopulmonary resuscitation; history of stroke; intracranial or intraspinal surgery or trauma; intracranial neoplasm

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Caution in IM administration of medications and severe hypertension, trauma, or surgery in previous 10 d; avoid dislodging possible deep vein thrombi; do not measure blood pressure in lower extremities; monitor therapy by measuring PT, aPTT, TT, or fibrinogen approximately 4 h after initiation of therapy

Streptokinase (Kabikinase, Streptase)

Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. An increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with IV infusion of streptokinase.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

250,000 U IV bolus followed by an infusion at 100,000 U/h for 1-3 d
Pediatric

Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Antifibrinolytic agents may decrease effects of streptokinase; heparin, warfarin, and aspirin may increase risk of bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active internal bleeding; intracranial neoplasm; aneurysm; diathesis; severe uncontrolled arterial hypertension

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in severe hypertension, IM administration of medications, and trauma or surgery in the previous 10 d; measure hematocrit, platelet count, aPTT, TT, PT, or fibrinogen levels before therapy; either TT or aPTT should be less than twice the reference range value following infusion of streptokinase and before (re)instituting heparin; do not take blood pressure in the lower extremities because it may dislodge a possible deep vein thrombi; PT, aPTT, TT, or fibrinogen should be monitored 4 h after initiation of therapy

Alteplase, tPA (Activase)

Thrombolytic agent for DVT or PE. A tissue plasminogen activator (tPA) produced by recombinant DNA and used in the management of acute myocardial infarction, acute ischemic stroke, and PE.
Safety and efficacy of this regimen with coadministration of heparin and aspirin during the first 24 h after symptom onset have not been investigated.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Front-loaded regimen not validated
100 mg IV over 2 h recommended for treatment of massive PE
For DVT, an infusion of 0.5-1.5 mg/h utilizing catheter-directed therapy has been used, depending on local expertise.Follow-up
Further Inpatient Care

* Admitted patients may be treated with a LMWH, fondaparinux, or unfractionated heparin. Warfarin 5 mg PO daily is initiated and overlapped for about 5 days until the INR is therapeutic >2 for at least 24 hours.
* If inpatient treatment is necessary, LMWH or fondaparinux is effective and obviates the need for intravenous infusions or serial monitoring of the aPTT.
* With the introduction of LMWH or fondaparinux, selected patients qualify for outpatient treatment only if adequate home care and close medical follow-up can be arranged. As discussed, subcutaneous unfractionated heparin may be substituted for LMWH or fondaparinux if insurance issues are a limiting factor. Outpatient therapy with unfractionated heparin carries a higher risk of heparin-induced thrombocytopenia and remains a second-line drug.
* At some centers, patients with isolated calf vein DVT are treated with full anticoagulant therapy for 3 months.
* For admitted patients treated with unfractionated heparin, the aPTT or heparin activity level must be monitored every 6 hours while the patient is taking intravenous 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 HIT.
* While the patient is initiating therapy with warfarin, the prothrombin time (PT, INR) must be monitored closely (daily or alternate days) until the target is achieved, then weekly for several weeks. When the patient is stable, monitor monthly. Inability to monitor INR precludes outpatient treatment of DVT.
* For the first episode of DVT, patients should be treated for 3-6 months. Recurrent episodes should be treated for at least 1 year.
* Significant bleeding (ie, hematemesis, hematuria, gastrointestinal hemorrhage) should be thoroughly investigated because anticoagulant therapy may unmask a preexisting disease (eg, cancer, peptic ulcer disease, arteriovenous malformation).

Further Outpatient Care

* Most patients with confirmed proximal vein DVT may be safely treated on an outpatient basis. Exclusion criteria for outpatient management are as follows:
o Suspected or proven concomitant PE
o Significant cardiovascular or pulmonary comorbidity
o Ileofemoral DVT
o Contraindications to anticoagulation
o Familial or inherited disorder of coagulation - ATIII deficiency, prothrombin 20210A, protein C or protein S deficiency, or factor V Leiden
o Familial bleeding disorder
o Pregnancy
o Morbid obesity >150 kg
o Renal failure (creatinine >2 mg%)
o Unavailable or unable to arrange close follow-up care
o Unable to follow instructions
o Homeless
o No contact telephone
o Geographic—too far from hospital
o Patient/family resistant to outpatient therapy
* Treatment of isolated calf vein DVT is best individualized, taking into account local preferences, patient reliability, the availability of follow-up care, and an assessment of ongoing risk factors.
* Patients with suspected or diagnosed isolated calf vein DVT may be discharged safely on a nonsteroidal anti-inflammatory drug (NSAID) or aspirin with close follow-up care and repeat diagnostic studies (ie, ultrasonography) in 7 days to evaluate for proximal extension.
* At certain centers, patients with isolated calf vein DVT are treated with full anticoagulant therapy.
* Patients with suspected DVT but with negative initial noninvasive study results need to be reassessed by their primary care provider within 7 days.
* Patients with ongoing risk factors need to be reevaluated at 1 week to detect proximal extension because of the limited accuracy of noninvasive tests for calf vein DVT.
* 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 deep venous thrombosis (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 (up to 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.25

Transfer

* Transfer may be necessary for patients with special concerns such as inherited coagulation disorders.
* Transfer may be required depending on local expertise for thrombolytic therapy or insertion of a venocaval filter.

Deterrence/Prevention

* Prophylaxis for DVT is required in all patients with risk factors. DVT prophylaxis for patients scheduled to undergo major surgery is well recognized.
* Recently, a large multicenter double-blind placebo-controlled trial showed that a single subcutaneous 40-mg daily dose of enoxaparin achieved a 63% reduction in the incidence of DVT/PE in general medical patients admitted to the hospital.26
* In the Women's Health Study, supplementation with vitamin E (alpha-tocopherol, 600 IU every other day) reduced the risk of venous thromboembolism in women, especially those with a prior history or genetic predisposition.27
* High-risk patients should also be prescribed a single prophylactic subcutaneous 40 mg dose of enoxaparin prior to a long plane trip (>6 h).

Complications

* Acute PE may still occur despite adequate anticoagulation.
* Hemorrhagic complications are the most common adverse effects of anticoagulant therapy. The risk of major hemorrhage while taking heparin is approximately 5%.
* The treatment of hemorrhage while taking heparin depends on the severity of the bleeding and the extent to which the 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 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 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 CNS hemorrhage.
* Additional complications include the following:
o Systemic embolism
o Chronic venous insufficiency
o Postphlebitic syndrome (ie, pain and edema in the affected limb without new clot formation)
o Soft tissue ischemia associated with massive clot and very high venous pressures - Phlegmasia cerulea dolens

Prognosis

* All patients with proximal vein DVT are at long-term risk of chronic venous insufficiency.
* Approximately 20% of untreated proximal (above the calf) DVTs progress to pulmonary emboli, and 10-20% of these are fatal. With anticoagulant therapy, the mortality rate is decreased 5- to 10-fold.

Patient Education

* Advise women taking estrogen of the risks and common symptoms of thromboembolic disease.
* Discourage prolonged immobility, particularly on plane rides and long car trips.
* For excellent patient education resources, visit eMedicine's Circulatory Problems Center and Lung and Airway Center. Also, see eMedicine's patient education articles Blood Clot in the Legs and Pulmonary Embolism.

Miscellaneous
Medicolegal Pitfalls

* Failure to consider the diagnosis in patients with risk factors
* Failure to recommend repeat noninvasive studies and reassessment in high-risk patients with negative findings on initial evaluations

Special Concerns

* Superficial thrombophlebitis
o Superficial thrombophlebitis is often associated with DVT in 2 specific settings. The following high-risk groups require further evaluation for DVT:
+ Superficial thrombophlebitis in the absence of coexisting venous varices and no other obvious etiology
+ Involvement of the greater saphenous vein above the knee, especially if it extends to the saphenofemoral junction: These latter patients should be treated as having proximal vein DVT and treated with full anticoagulant therapy.
o Uncomplicated superficial thrombophlebitis may be treated symptomatically with heat, NSAIDs, and compression hose. Bed rest is not recommended.
o 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.
* Axillary/subclavian vein thrombosis
o 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 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.
o 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.
o 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.
o 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.
o 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.
o 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.