Deep Venous Thrombosis and Thrombophlebitis

Author: Donald Schreiber, MD, CM, Assistant Professor of Surgery, Stanford University School of Medicine; Research Director, Division of Emergency Medicine, Stanford University Hospital

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

Editor(s): Francis Counselman, MD, Program Director, Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Gary Setnik, MD, Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Barry Brenner, MD, PhD, Chairman, Department of Emergency of Medicine, Professor, Departments of Emergency Medicine and Internal Medicine, University of Arkansas for Medical Sciences INTRODUCTION Section 2 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Deep venous thrombosis (DVT) and its sequela, pulmonary embolism, is the leading cause of preventable in-hospital mortality in the US. Although pulmonary embolism is discussed elsewhere in this text, it must be emphasized that it is primarily a complication of DVT.

The first reference to peripheral venous disease is recorded on the Ebers papyrus in 1550 BC, which documents the potential 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 pulmonary embolism. Heparin only was introduced to clinical practice in 1937. Over the last 25 years, considerable progress has been made in the pathophysiology, diagnosis, and treatment of DVT.

Pathophysiology: Virchow triad as first formulated (venous stasis, vessel wall injury, and a hypercoagulable state) is still the primary mechanism for the development of venous thrombosis. The relative importance of each factor still is debated. 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 minimizing 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, as seen with hip surgery or catheter-induced DVT. 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 the 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 pulmonary embolism. 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 and suggests that propagation proximally may occur rapidly and that fatal pulmonary embolism arising from isolated calf vein DVT is a significant risk.

The current diagnostic and therapeutic management of DVT is influenced strongly 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:

In the US: 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 underestimate the true incidence of DVT suggest that about 80 cases per 100,000 persons occur annually. Approximately 1 person in 20 develops DVT over her or his lifetime, and 600,000 hospitalizations for DVT occur annually in the US. 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 suffer from venous stasis and varying degrees of venous insufficiency.

Mortality/Morbidity: Death from DVT is attributed to massive pulmonary embolism, which causes 200,000 deaths annually in the US. Pulmonary embolism is the leading cause of preventable in-hospital mortality.

Sex: Male-to-female ratio is 1.2:1.

Age: DVT usually affects individuals older than 40 years. CLINICAL Section 3 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

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 repeatedly have documented this inherent difficulty of the clinical diagnosis of lower extremity DVT. Many patients are asymptomatic, however, the history may include the following: Edema, principally unilateral, is the most specific symptom. Massive edema with cyanosis and ischemia (phlegmasia cerulea dolens) is rare. Leg pain occurs in 50%, but this is entirely nonspecific. Pain can occur on dorsiflexion of the foot (Homans sign). Tenderness occurs in 75% of patients, but it also is found in 50% of patients without objectively confirmed DVT. Clinical signs and symptoms of pulmonary embolism as the primary manifestation occur in 10% of patients with confirmed DVT. The pain and tenderness associated with DVT usually does not correlate with the size, location, or extent of the thrombus. 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 Tenderness, if present, usually is confined to the calf muscles or over the course of the deep veins in the thigh.

Pain and/or tenderness away from these areas is not consistent with venous thrombosis and usually indicates another diagnosis. Homans sign Discomfort in the calf muscles on forced dorsiflexion of the foot with the knee straight has been a time-honored sign of DVT. However, this sign is present in less than one third of patients with confirmed DVT. It also is found in more than 50% of patients without DVT. It is therefore very nonspecific. Venous distension and prominence of the subcutaneous veins Superficial thrombophlebitis is characterized by the finding of a palpable, indurated, cordlike, tender subcutaneous venous segment. Patients with superficial thrombophlebitis without coexisting varicose veins and with no other obvious etiology (eg, IV catheters, IV drug abuse, soft tissue injury) are at high risk because associated DVT is found in as many as 40% of these patients. Patients with superficial thrombophlebitis extending to the saphenofemoral junction are also at higher risk for associated DVT. Fever: Fever, usually low grade, may be present. High fever is usually indicative of an infectious process such as cellulitis or lymphangitis. Phlegmasia cerulea dolens Patients with venous thrombosis may develop variable discoloration of the lower extremity. The most common abnormal hue is reddish purple from venous engorgement and obstruction.

In rare cases, the leg is cyanotic from massive ileofemoral venous obstruction. This ischemic form of venous occlusion originally was 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 Painful white inflammation originally was used to describe massive ileofemoral venous thrombosis and associated arterial spasm. The affected extremity is often pale with poor or even absent distal pulses. The physical findings may suggest acute arterial occlusion, but the presence of swelling, petechiae, and distended superficial veins point to this condition. Clinical findings of pulmonary embolism These findings are the primary manifestation of about 10% of patients with DVT. In patients with angiographically proven pulmonary embolism, DVT is found in 45-70%. In the vast majority of these patients, the 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: 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 Medical

Cancer Previous DVT

Cerebrovascular accident

Acute myocardial infarction (AMI)

Congestive heart failure (CHF)

Sepsis

Nephrotic syndrome

Ulcerative colitis Trauma

Multiple trauma CNS/spinal cord injury

Burns

Lower extremity fractures

Vasculitis

Systemic lupus erythematosus (SLE) and the lupus anticoagulant Behet syndrome

Homocystinuria

Hematologic

Polycythemia rubra vera Thrombocytosis

Inherited disorders of coagulation/fibrinolysis

Antithrombin III deficiency

Protein C deficiency

Protein S deficiency

Factor V Leyden

Dysfibrinogenemias and disorders of plasminogen activation Drugs/medications

IV drug abuse Oral contraceptives

Estrogens

Heparin-induced thrombocytopenia

The clinical assessment of patients with suspected DVT is often difficult because of the interplay between risk factors and the nonspecific nature of the physical findings. Clinicians have observed that often a discordance is present 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 duplex ultrasound study.

In this case, the probability of DVT is still greater than 20% when the known sensitivity, specificity, and negative likelihood ratio of duplex ultrasound are considered. It was recognized that having an objective method to determine pretest probability would simplify clinical management. A clinical prediction guide that quantifies the pretest probability was developed. 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. Wells Clinical Prediction Guide for DVT

Clinical Parameter Score Active cancer (treatment ongoing, or within 6 months or palliative) 1 Paralysis or recent plaster immobilization 1 Recently bedridden for >3 days or major surgery <4 weeks 1 Localized tenderness along the distribution of the deep venous system 1 Entire leg swelling 1 Calf swelling >3 cm compared to the asymptomatic leg 1 Pitting edema (greater in the symptomatic leg) 1 Collateral superficial veins (nonvaricose) 1

Alternative diagnosis (as likely or > that of DVT) -2

Total of Above Score

High probability: Score 3 Moderate probability: Score = 1 or 2 Low probability: Score 0

Adapted from Anand SS, et al. JAMA. 1998; 279 [14];1094

DIFFERENTIALS Section 4 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Cellulitis Pulmonary Embolism Thrombophlebitis, Septic Thrombophlebitis, Superficial

Other Problems to be Considered:

In approximately 70% of patients with clinically suspected DVT, alternate diagnoses ultimately are 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

Quick Find Author Information Introduction

Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Click for related images.

Related Articles Cellulitis

Pulmonary Embolism

Thrombophlebitis, Septic

Thrombophlebitis, Superficial

Continuing Education CME available for this topic. Click here to take this CME.

Patient Education Click here for patient education.

WORKUP Section 5 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Lab Studies:

Hematologic and coagulation studies are not required prior to confirming the diagnosis. A number of studies have evaluated the use of D-dimer, a fibrin degradation product, in the diagnosis of DVT. It has been shown to be 93% sensitive for proximal vein thrombosis, but it is relatively nonspecific. In some centers, it has been used as a screening test for DVT. Some authors have recommended incorporating D-dimer results

into a management strategy. Different D-dimer assays are available with considerable variation in sensitivity and specificity. The older quantitative enzyme-linked immunoassay (ELISA) is very accurate but time consuming and not practical for use in the ED. A new rapid qualitative ELISA assay is now available. The older qualitative latex agglutination assay is not accurate and should not be used for treating patients with suspected DVT. A rapid bedside qualitative RBC agglutination assay (SimpliRED) is available and is reasonably sensitive for proximal DVT but less so for calf vein DVT. All D-dimer assays are dependent on the size of the clot. D-dimer assays are not "clot specific" and are positive in many other conditions associated with DVT such as recent surgery, trauma, MI, pregnancy, and metastatic cancer. This explains their lack of specificity. In patients with low pretest probability for DVT, a negative D-dimer as measured by the whole blood RBC agglutination assay reduces the probability of DVT to less than 1%. Some physicians may choose to forego objective ultrasound testing in this scenario. Protein S, protein C, antithrombin III, factor V Leyden, prothrombin 20210A mutation, and antiphospholipid antibodies can be measured. Deficiencies of these factors produce a hypercoagulable state. These are rare causes of DVT. Laboratory investigations for these abnormalities primarily are indicated when DVT is diagnosed in patients younger than 35 years or

when venous thrombosis is detected in unusual sites. Imaging Studies:

Due to the inherent inaccuracy of clinical diagnosis, the history, physical examination, and assessment of risk factors should be used to determine who requires further objective diagnostic testing. Diagnosing DVT and committing patients to the risks of anticoagulation without confirmatory objective testing are unacceptable. Contrast venography 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 reliability, and lack of availability, venography is either contraindicated or nondiagnostic in as many as 20-25% of patients. As a result, noninvasive studies essentially have replaced venography as the initial diagnostic test of choice.

Duplex ultrasonography and impedance plethysmography (IPG) are the noninvasive tests that have been investigated the most. Duplex ultrasound Technological advances in ultrasound have permitted the combination of real-time ultrasonic imaging with Doppler flow studies (duplex ultrasound). The major ultrasound 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. Many studies have confirmed the diagnostic sensitivity and specificity of duplex ultrasound for proximal vein thrombosis. Sensitivity and specificity for Duplex ultrasound are 98%.

Duplex ultrasound is also helpful to differentiate venous thrombosis from hematoma, Baker cyst, abscess, and other causes of leg pain and edema. The primary disadvantage of duplex ultrasound 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 hard to detect. In patients with suspected acute recurrent DVT, duplex ultrasound may not be able to differentiate between old and new clots. Ultrasound equipment is expensive, and accuracy may vary depending on local expertise. Impedance plethysmography In some countries, 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 related directly 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 studies from abnormal results. 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. Falsepositive results occur in the setting of significant CHF and raised central venous pressure as well as with severe arterial insufficiency. MRI MRI increasingly has been investigated for evaluation of suspected DVT. In limited studies, the accuracy approaches that of the criterion standard, contrast venography.

MRI is the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis.

In the second and third trimester of pregnancy, MRI is more accurate than duplex ultrasound because the gravid uterus alters Doppler venous flow characteristics.

In suspected calf vein thrombosis, MRI is more sensitive than any other noninvasive study.

Expense, lack of general availability, and technical issues limit its use.

Nuclear medicine imaging studies: Nuclear medicine studies with I125labeled fibrinogen no longer are recommended for ED patients. It is relatively insensitive for proximal vein thrombosis, takes longer than 24 hours to obtain results, and a significant number of falsepositive studies are obtained. I125-labeled fibrinogen is no longer available in the US. Summary - Which test is best? When directly compared, duplex ultrasound has superior sensitivity and specificity over IPG. Controversy still exists over the use of noninvasive studies such as duplex ultrasound for the diagnosis of suspected DVT. Recognizing that duplex ultrasound is relatively insensitive for calf vein thrombosis only matters if the clinician is inclined to anticoagulate patients with calf vein DVT. 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 is irrelevant. 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 incorrectly recommend the routine use of contrast venography rather than a noninvasive study for suspected DVT on the basis of low sensitivity that has been reported on studies of hospitalized patients posthip surgery.

In ambulatory outpatients with suspected DVT, the sensitivity of

duplex ultrasound for proximal vein thrombosis is 98%, and it remains the initial diagnostic test of choice. Simplified Clinical Management Strategy for Patients with Suspected DVT

Using the pretest probability score calculated from the Wells Clinical Prediction rule, patients are stratified into 3 risk groups high, moderate, or low.

The results from duplex ultrasound are incorporated as follows:

If the patient is high or moderate risk and the duplex ultrasound study is positive, treat for DVT.

If the duplex study is negative and the patient is low risk, DVT has been ruled out.

When discordance exists between the pretest probability and the duplex study result, further evaluation is required.

If the patient is high risk but the ultrasound study was negative, the patient still has a significant probability of DVT. Some authors recommend a venogram to rule out a calf vein DVT that the ultrasound study did not detect. Some authors recommend surveillance with repeat clinical evaluation and ultrasound in 1 week. Others use the results of a D-dimer assay to guide management. A negative D-dimer in

combination with a negative ultrasound study significantly lowers the probability of DVT.

If the patient is low risk but the ultrasound study is positive, some authors recommend a second confirmatory study such as a venogram before treating for DVT and committing the patient to the risks of anticoagulation.

If the patient is moderate risk and the ultrasound study is negative, repeat clinical evaluation and ultrasound in 1 week is recommended.

It is important to realize that the clinical prediction rule was developed in a specific subgroup of patients. Excluded from the model were patients with recurrent DVT, patients with suspected coexistent pulmonary embolism, and patients already on anticoagulants. Therefore, the evaluation and subsequent treatment of this last subgroup of patients must be individualized. TREATMENT Section 6 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Emergency Department Care: The primary objectives of the treatment of DVT are to prevent pulmonary embolism, reduce morbidity, and prevent

or minimize the risk of developing the postphlebitic syndrome.

Anticoagulation Thrombolytic therapy for DVT 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 pulmonary embolism. The rationale for thrombectomy is to restore venous patency and valvular function. Thrombectomy alone is not indicated, because rethrombosis occurs very frequently. Heparin therapy is a necessary adjunct. Thrombectomy is best reserved for patients with massive ileofemoral vein thrombosis (phlegmasia cerulea dolens) when limb viability is at risk. Filters for DVT The concept of inferior vena cava filters arose from the recognition of the late complications of surgical ligation of the inferior vena cava as first proposed by Homans in 1934. Today, intracaval devices introduced intravenously at a remote site and floated into position using fluoroscopy is the procedure of choice. The Kim-Ray-Greenfield filter is preferred because the long-term patency rates are much higher. Indications for a filter are severe hemorrhagic complications on anticoagulant therapy, other absolute contraindications to anticoagulation, new or recurrent venous thrombosis, or pulmonary

embolism despite adequate anticoagulation. Compression stockings (routinely recommended) Ambulation: Controversy exists regarding the role of ambulation in the therapy of DVT. In North America, bed rest and decreased ambulation usually are recommended theoretically to prevent embolization. In Europe, increased ambulation usually is recommended to avoid further venous stasis and propagation of the thrombus. Consultations:

Hematology Vascular surgery Radiology Nuclear medicine MEDICATION Section 7 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Goals of pharmacotherapy in treating venous thrombosis are to reduce morbidity, prevent the postphlebitic syndrome, prevent the development of pulmonary embolism, and to attain these goals with a minimum number of adverse effects and cost.

Drug Category: Anticoagulants -- Anticoagulation remains the mainstay

of initial treatment for DVT. Regular unfractionated heparin was the standard of care until the recent introduction of low molecular weight heparin (LMWH). 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 this is 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 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.

Heparin's anticoagulant effect is related directly 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.

The optimal regimen for the treatment of DVT is anticoagulation with heparin or an LMWH followed by full anticoagulation with oral warfarin for 3-6 months. Some evidence exists that even longer anticoagulation with warfarin is appropriate in certain cases.

Warfarin therapy is overlapped with heparin for 4-5 days until the INR is therapeutically elevated to between 2-3. It is necessary to overlap heparin 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 definitely is indicated for patients with recurrent venous thrombosis and/or persistent or irreversible risk factors.

When IV unfractionated heparin is initiated for DVT, the goal is to achieve and maintain an elevated aPTT of at least 1.5 times control. Heparin pharmacokinetics are complex, with a half-life of 60-90 minutes. After an initial bolus of 80 U/kg, a constant maintenance infusion of 18 U/kg is initiated. The aPTT is checked 6 hours after the bolus and adjusted accordingly. The aPTT is repeated every 6 hours until 2 successive aPTTs are therapeutic. Thereafter, the aPTT

is monitored every 24 hours as well as the hematocrit and platelet count.

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, the subset of patients who develop thrombosis is unpredictable. All patients who develop thrombocytopenia while on heparin are at risk. Alternatives include the substitution of porcine for bovine heparin, the use of LMWH, or initiation of therapy with warfarin alone.

LMWH is prepared by selectively treating unfractionated heparin to isolate the low (<9,000 Da) molecular weight 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 is administered SC, and its half-life permits single or twice daily dosing. Its use in the outpatient treatment of DVT and pulmonary embolism has been evaluated in a number of studies.

At the present time, 3 LMWH preparations, Enoxaparin, Dalteparin, and Ardeparin, have received FDA approval for the treatment of DVT. Tinzaparin has been approved for in-hospital treatment of DVT.

The increased bioavailability and prolonged half-life of LMWH allow

for outpatient treatment of DVT using once or twice daily SC treatment regimens. Outpatient treatment of acute DVT using LMWH has been evaluated successfully in a number of studies and is currently the treatment option of choice if the patient meets the necessary criteria. Outpatient management is not recommended if the patient has proven or suspected concomitant pulmonary embolism, significant comorbidities, extensive ileofemoral DVT, morbid obesity, renal failure, or poor follow-up.Drug Name Heparin (Hep-Lock) -- 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. Adult Dose 80 U/kg IV bolus, followed by 18-U/kg/h maintenance infusion Monitor aPTT and titrate maintenance dose to effect Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity; subacute bacterial endocarditis; severe liver disease; hemophilia; active bleeding; history of heparin-induced thrombocytopenia Interactions Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity Pregnancy A - Safe in pregnancy 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

Drug Name Warfarin (Coumadin) -- Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Dose must be individualized and adjusted to maintain INR between 2-3. Adult Dose 2-10 mg/d PO Pediatric Dose Weight-based dose of 0.05-0.34 mg/kg/d; adjust according to desired INR Infants may require doses at or near high end of this range Contraindications Documented hypersensitivity; severe liver or kidney disease; risk of CNS hemorrhage; cerebral aneurysms; open wounds or bleeding of GI, GU, or respiratory tract Interactions Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate Medications that may increase anticoagulant effects of warfarin include oral 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 Pregnancy D - Unsafe in pregnancy Precautions Do not switch brands after achieving therapeutic

response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis Drug Name Enoxaparin (Lovenox) -- LMWH used in treatment of DVT and pulmonary embolism 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. Adult Dose 1 mg/kg SC bid; alternatively, administer 1.5 mg/kg SC qd Pediatric Dose Not established The following doses have been suggested: <2 months: 0.75 mg/kg/dose bid 2 months to 18 years: 0.5 mg/kg/dose bid Contraindications Documented hypersensitivity; major bleeding; history of heparin-induced thrombocytopenia Interactions Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases 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

Drug Name Tinzaparin (Innohep) -- Used in hospitalized patients. 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. Adult Dose 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 d) Pediatric Dose Not established; adult dose suggested Contraindications Documented hypersensitivity; major bleeding, heparin-induced thrombocytopenia (current or history of) Interactions Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated low-molecular-weight heparins; 1 mg of protamine sulfate will reverse effect of approximately 100 U of tinzaparin if significant bleeding complications develop Drug Category: Thrombolytics -- Offer significant advantages over conventional anticoagulant therapy. Advantages include prompt resolution of symptoms, prevention of pulmonary embolism, restoration

of normal venous circulation, preservation of venous valvular function, and prevention of postphlebitic syndrome. Thrombolytic therapy does not prevent clot propagation, rethrombosis, or subsequent embolization. Heparin therapy and oral anticoagulant therapy always must follow a course of thrombolysis.

Unfortunately, the majority of 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 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 seen on the posttreatment venogram is predictive of future venous valvular insufficiency and late (5-10 y) development of postphlebitic syndrome. Preliminary evidence suggests the incidence of postphlebitic syndrome at 3 years is reduced by half but certainly not entirely eliminated.

The hemorrhagic complications of thrombolytic therapy are formidable (about 3 times higher), including the small but potentially fatal risk of intracerebral hemorrhage. The uncertainty regarding

thrombolytic therapy likely will continue. Currently, thrombolytic therapy is not recommended routinely for DVT at most centers but should be considered in patients with massive ileofemoral vein thrombosis or in young patients with acute onset of extensive DVT.Drug Name 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. Advantage is that it is nonantigenic. More expensive than streptokinase, which limits its use. When used for purely local fibrinolysis, given as local infusion directly into area of thrombus and with no bolus. Dose should be adjusted to achieve clot lysis or patency of affected vessel. Adult Dose 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 Dose Administer as in adults Contraindications Documented hypersensitivity; internal bleeding; recent trauma including cardiopulmonary resuscitation; history of cerebrovascular accident; intracranial or intraspinal surgery or trauma; intracranial neoplasm Interactions Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding

complications Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Caution in patients receiving intramuscular administration of medications and those with severe hypertension or trauma or surgery in previous 10 d; avoid dislodging a possible deep vein thrombi; do not measure blood pressure in lower extremities; monitor therapy by performing PT, aPTT, TT, or fibrinogen approximately 4 h after initiation of therapy Drug Name 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 intravenous infusion of streptokinase. Adult Dose 250,000 U IV bolus followed by an infusion at 100,000 U/h for 1-3 d Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity; active internal bleeding; intracranial neoplasm; aneurysm; diathesis; severe uncontrolled arterial hypertension Interactions Antifibrinolytic agents may decrease effects of streptokinase; heparin, warfarin, and aspirin may increase risk of bleeding Pregnancy C - Safety for use during pregnancy has not been established. Precautions Caution in severe hypertension, intramuscular

administration of medications, and trauma or surgery in the previous 10 d; measure hematocrit, platelet count, aPTT, TT, PT, or fibrinogen levels before therapy is implemented; either TT or aPTT should be less than twice the normal control value following infusion of streptokinase and before (re)instituting heparin; do not take blood pressure in the lower extremities as it may dislodge a possible deep vein thrombi; PT, aPTT, TT, or fibrinogen should be monitored 4 h after initiation of therapy Drug Name Alteplase, t-PA (Activase) -- Thrombolytic agent for DVT or pulmonary embolism. A tissue plasminogen activator (tPA) produced by recombinant DNA and used in the management of acute ischemic stroke, AMI, and pulmonary embolism. Safety and efficacy of this regimen with coadministration of heparin and aspirin during the first 24 h after symptom onset have not been investigated. Adult Dose Front-loaded regimen recommended 15 mg IV bolus initially followed by 50 mg IV over the next 30 min and then 35 mg IV over the next 1 h Pediatric Dose Not established Contraindications Documented hypersensitivity; active internal bleeding; intracranial or intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; <2 mo history of cerebrovascular accident; bleeding diathesis; severe uncontrolled hypertension; also avoid with intracranial hemorrhage when performing pretreatment evaluation, recent intracranial surgery, suspicion of

subarachnoid hemorrhage, or serious head trauma or recent previous stroke; do not administer with a history of intracranial hemorrhage, uncontrolled hypertension, intracranial neoplasm, seizure at onset of stroke, active internal bleeding, arteriovenous malformation or aneurysm, or bleeding diathesis Interactions Drugs that alter platelet function (aspirin, dipyridamole, abciximab) may increase risk of bleeding before, during, or after alteplase therapy; may give heparin with and after alteplase infusions to reduce risk of rethrombosis; either heparin or alteplase may cause bleeding complications Pregnancy C - Safety for use during pregnancy has not been established. Precautions Monitor for bleeding, especially at arterial puncture sites, with coadministration of vitamin K antagonists; control and monitor blood pressure frequently during and following alteplase administration (when managing acute ischemic stroke); do not use >0.9 mg/kg to manage acute ischemic stroke; doses >0.9 mg/kg may cause ICH FOLLOW-UP Section 8 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Inpatient Care:

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

Suspected or proven concomitant pulmonary embolism

Significant cardiovascular or pulmonary comorbidity

Morbid obesity

Renal failure

Unavailable or unable to arrange close follow-up care

Patients are treated with a low molecular weight heparin and instructed to initiate therapy with warfarin 5 mg PO the next day. Low molecular weight heparin and warfarin are overlapped for about 5 days until the international normalized ratio (INR) is therapeutic.

If inpatient treatment is necessary, low molecular weight heparin is effective and obviates the need for IV infusions or serial monitoring of the PTT. With the introduction of low molecular weight heparin, selected patients qualify for outpatient treatment only if adequate home care

and close medical follow-up care can be arranged. At some centers, patients with isolated calf vein DVT are admitted for full anticoagulant therapy. Many physicians do not treat calf vein DVT with anticoagulation unless proximal extension is documented objectively with close clinical surveillance. The activated partial thromboplastin time (aPTT) must be monitored every 6 hours while the patient is on IV heparin until the dose stabilizes. Platelets also should be monitored and heparin discontinued if platelets fall below 75,000. While on warfarin, the prothrombin time (PT) must be monitored daily until target 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, patients should be treated for 3-6 months. Subsequent episodes should be treated for at least 1 year. Significant bleeding (ie, hematemesis, hematuria, gastrointestinal hemorrhage) should be investigated thoroughly since anticoagulant therapy may unmask a preexisting disease (eg, cancer, peptic ulcer disease, arteriovenous malformation). Further Outpatient Care:

Treatment for 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 in 37 days to detect proximal extension. At certain centers, patients with isolated calf vein DVT are admitted for full anticoagulant therapy. Patients with suspected DVT but negative noninvasive studies need to be reassessed by their primary care provider within 3-7 days. Patients with ongoing risk factors may need to be restudied at that time to detect proximal extension because of the limited accuracy of noninvasive tests for calf vein DVT. Transfer:

Transfers may be necessary for patients with special concerns such as those with inherited coagulation disorders. Transfers may be required depending on local expertise for treatment with thrombolytics, surgical therapy, or insertion of a filter. Deterrence/Prevention:

Prophylaxis for DVT is required for all patients who develop risk factors. DVT prophylaxis for patients scheduled to undergo major surgery is well recognized. Recently a large multicenter double-blind placebo-controlled trial showed a 63% reduction in the incidence of DVT/pulmonary embolism in

general medical patients admitted to the hospital. Complications:

Acute pulmonary embolism still may occur despite adequate anticoagulation. Hemorrhagic complications are the most common adverse effects of anticoagulant therapy. The risk of hemorrhage on heparin is approximately 5%. The treatment of hemorrhage while on 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 normal 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 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 lifethreatening hemorrhage is managed with fresh frozen plasma in

addition to vitamin K. Additional complications include the following: Systemic embolism Chronic venous insufficiency Postphlebitic syndrome (ie, pain and edema in the affected limb without new clot formation) Soft-tissue ischemia associated with massive clot and very high venous pressures - Phlegmasia cerulea dolens (very rare but should be considered a surgical emergency) Prognosis:

All patients with proximal vein DVT are at long-term risk of developing chronic venous insufficiency. About 20% of untreated proximal (above the calf) DVTs progress to pulmonary emboli, and 10-20% of these are fatal. With aggressive anticoagulant therapy, the mortality is decreased 5- to 10-fold. DVT confined to the calf virtually never causes clinically significant emboli and thus does not require anticoagulation. However, calf DVTs occasionally propagate into the proximal system. Therefore, suspected calf DVTs should be observed every 3-5 days for 10 days and treated aggressively if they propagate into the popliteal or femoral system. 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. MISCELLANEOUS Section 9 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal 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 initial evaluations Special Concerns:

Superficial thrombophlebitis Superficial thrombophlebitis often is 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 Uncomplicated superficial thrombophlebitis may be treated symptomatically with heat, NSAIDs, and compression hose. Bed rest is not recommended. Some centers recommend full anticoagulation even with negative noninvasive studies for the high-risk groups mentioned above. An alternative approach involves symptomatic care alone with close follow-up and repeat noninvasive testing in 24-72 hours. Full anticoagulation then is reserved only for those patients with proven proximal vein DVT. Axillary/subclavian vein thrombosis This first was described by Paget (1875) and von Schrtter (1884) and is sometimes referred to as Paget-von Schrtter syndrome. The pathophysiology is similar to that of DVT, and the etiologies overlap. The incidence is lower than DVT, of the lower extremities because of decreased hydrostatic pressure, fewer venous valves, higher rates of blood flow, and less frequent immobility of the upper arm. Thoracic outlet compression from cervical ribs or congenital webs may precipitate axillary/subclavian venous thrombosis. Catheter-induced thrombosis is increasingly a common cause of this condition. The increased use of subclavian catheters for chemotherapy and parenteral nutrition has resulted in a dramatic increased incidence of proven

thrombosis.

Similarly, pulmonary artery catheters are associated with a high incidence of internal jugular and subclavian vein thrombosis. Pulmonary embolism occurs in approximately 10% of patients. Fatal or massive pulmonary embolism is extremely rare. Ultrasonography and venography are the diagnostic tests of choice. Ultrasonography may be falsely negative because of collateral blood flow. Duplex ultrasound is accurate for the evaluation of the internal jugular vein and its junction with the subclavian vein where the innominate vein begins. Thrombolytic therapy is the treatment of choice for axillary/subclavian venous thrombosis. Restoration of venous patency is more critical for the prevention of chronic venous insufficiency in the upper extremity. Thrombolysis is best accomplished with local administration of the thrombolytic agent directly at the thrombus. After completion of a venographic study, a catheter is floated up to the site of the clot, and the thrombolytic agent is administered as a direct infusion. Venographic assessment for clot lysis is repeated every 4-6 hours until venous patency is restored. Heparin usually is given concurrently to prevent rethrombosis. In the presence of anatomic abnormalities, surgical therapy is recommended to minimize long-term morbidity and recurrence. Catheterinduced thrombosis may require removal of the device. Locally infused thrombolytic agents have been used successfully and are currently the treatment of choice.

BIBLIOGRAPHY Section 10 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Anand SS, Wells PS, Hunt D, et al: Does this patient have deep vein thrombosis? JAMA 1998 Apr 8; 279(14): 1094-9[Medline]. Bounameaux H, de Moerloose P, Perrier A, Reber G: Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemost 1994 Jan; 71(1): 1-6[Medline]. Carter CJ: The natural history and epidemiology of venous thrombosis. Prog Cardiovasc Dis 1994 May-Jun; 36(6): 423-38[Medline]. Cogo A, Bernardi E, Prandoni P, et al: Acquired risk factors for deep vein thrombosis in symptomatic outpatients. Arch Intern Med 1994; 151: 164-168[Medline]. Ginsberg JS, Wells PS, Hirsh J, et al: Reevaluation of the sensitivity of impedance plethysmography in the diagnosis of clinically suspected deep vein thrombosis. Arch Intern Med 1994; 154: 1930[Medline]. Goldhaber SZ, Simons GR, Elliott CG, et al: Quantitative plasma Ddimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism. JAMA 1993 Dec 15; 270(23): 2819-22 [Medline]. Heijboer H, Buller HR, Lensing AW, et al: A comparison of real-time

compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993 Nov 4; 329(19): 1365-9[Medline]. Hirsh J, Hull RD, Raskob GE: Clinical features and diagnosis of venous thrombosis. J Am Coll Cardiol 1986 Dec; 8(6 Suppl B): 114B-127B [Medline]. Hirsh J, Dalen JE, Deykin D, Poller L: Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992 Oct; 102(4 Suppl): 337S-351S[Medline]. Hull RD, Raskob GE, Pineo GF, et al: Subcutaneous low-molecularweight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992 Apr 9; 326 (15): 975-82[Medline]. Hyers TM: Venous thromboembolism. Am J Respir Crit Care Med 1999 Jan; 159(1): 1-14[Medline]. Koopman MM, Van Beek EJ, Ten Cate JW: Diagnosis of deep vein thrombosis. Prog Cardiovasc Dis 1994; 37: 1-12[Medline]. Lensing AW, Prins MH, Davidson BL, Hirsh J: Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995 Mar 27; 155(6): 601-7[Medline]. Moser KN, Lemoine JR: Is embolic risk conditioned by location of deep venous thrombosis? Ann Intern Med 1981; 94: 439[Medline]. Philbrick JT, Becker DM: Calf deep vein thrombosis: A wolf in sheep's clothing? Arch Intern Med 1988; 148: 2131-2138[Medline]. Redman HC: Deep venous thrombosis: Is contrast venography still the diagnostic gold standard? Radiology 1988; 168: 277[Medline].

Samama MM, Cohen AT, Darmon JY, et al: A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999 Sep 9; 341(11): 793-800[Medline]. Schreiber DH: Venous disease of the extremities. In: Rosen P, et al, eds. Emergency Medicine: Concepts and Clinical Practice. 1992: 14511486. Tschersich HU: Diagnosis of acute deep venous thrombosis of the lower extremities: prospective evaluation of color Doppler flow imaging versus venography. Radiology 1995 Apr; 195(1): 289[Medline]. Turpie AG, Levine MN, Hirsh J, et al: Tissue plasminogen activator (rt-PA) vs heparin in deep vein thrombosis. Results of a randomized trial. Chest 1990 Apr; 97(4 Suppl): 172S-175S[Medline]. Weitz JI: Low-molecular-weight heparins. N Engl J Med 1997 Sep 4; 337 (10): 688-98[Medline]. Wells PS, Brill-Edwards P, Stevens P, et al: A novel and rapid wholeblood assay for D-dimer in patients with clinically suspected deep vein thrombosis. Circulation 1995 Apr 15; 91(8): 2184-7[Medline]. Wells PS, Anderson DR, Bormanis J, et al: Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997 Dec 20-27; 350(9094): 1795-8[Medline]. Wolf H: Low-molecular-weight heparin. Med Clin North Am 1994 May; 78 (3): 733-43[Medline].