Protocols for Deep Venous Thrombosis (DVT): A State-of-the-Art Review Part II: Patient Management, Anticoagulation, and Special Considerations

Author: Stephen A. Colucciello, MD, FACEP, Assistant Clinical Professor of Emergency Medicine, University of North Carolina Medical School, Chapel Hill, North Carolina; Director, Clinical Services Trauma Coordinator, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC.

Peer Reviewer: Charles Stewart, MD, FACEP, Emergency Physician, Colorado Springs, CO.

The treatment landscape for managing patients with deep venous thrombosis (DVT) is evolving at a rapid pace. The most important studies affecting current approaches to therapy are those comparing and evaluating the efficacy of unfractionated heparin (UH) vs. low molecular weight heparin (LMWH) for management of patients with DVT, both in and out of the hospital.

These trials, which are impressive in their support of the saftey, suitability, and efficacy of LMWHs, have presented new challenges for the emergency medicine community. In particular, new developments in the management of DVT require emergency physicians to risk stratify patients into those who require hospitalization and those who are amenable to outpatient treatment. In this regard, recent approval of the LMWH, enoxaparin, for out-of-hospital treatment of DVT has positive pharmacoeconomic consequences that must be considered in the equation for DVT management.

Risk stratification of these patients will include a detailed history and evaluation that considers the presence of underlying co-morbid conditions, hemodynamic stability of the patient, exclusion of pulmonary embolism, location of the thrombosis, ability of patient to self-administer LWMH on a home basis, and adequate follow-up and support.

The second part of this two-part series on DVT examines the pharmacotherapeutic options available for DVT management. The roles of heparin, LMWHs, and warfarin are examined in detail, and indications for procedural interventions are also discussed. Finally, a management algorithm outlining an outcome-effective approach to managing DVT with LMWH is presented.

—The Editor

Management Principles

The patient with deep venous thrombosis (DVT) rarely requires immediate life-saving intervention. Nevertheless, management protocols must be systematic and precise. (See Table 1.) Two life-threatening conditions are pulmonary embolism (PE) and phlegmasia dolens. If either diagnosis is clinically obvious, heparin should be started prior to imaging studies. Hypotensive patients with these conditions require rapid crystalloid infusion and thrombolytics.

Table 1. Management
Superficial venous thrombosis
• Use duplex scan to screen for involvement of deep system
• Elevation, non-steroidal anit-inflammatory drugs
Deep venous thrombosis
• Begin warfarin on the first hospital day or in the ED
• Low-molecular-weight heparin—more effective and safer than standard heparin
• Enoxaparin recently approved in the United States for treatment of DVT
• Heparin 80 U/kg load, 18 U/kg/hr drip
• ? Thrombolysis for severe disease in young adults
• Vana cava filter if thrombosis in presence of adequate anticoagulation
Phlegmasia dolens
• Fluid resuscitation
• Heparinization before imaging studies
• Thrombolysis for patients who do not respond rapidly to heparin
• Thrombectomy for patients unresponsive to thrombolysis
Upper extremity thrombosis
• Diagnose with duplex scan
• Catheter directed thrombolysis
Calf thrombi
• Anticoagulate or perform serial studies to detect propagation
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Patients with suspected DVT require objective testing, preferably with duplex scanning. If venous thrombosis is confirmed, contraindications to anticoagulation should be identified. Patients with absolute contraindications to heparin require vena cava interruption.1 The filter is 95% effective in preventing PE and has a 10% complication rate on insertion. Since these outcomes are similar to those seen with anticoagulation, some authorities recommend that the filter be the primary intervention for recurrent DVT.2 In particular, patients with malignancies benefit from this procedure.3 It should be stressed that filter insertion, itself, is associated with a 22% incidence of DVT at the puncture site.4 Anticoagulation is the mainstay of treatment. Specific therapeutic agents are discussed below.

Heparin

Heparin activates antithrombin III to prevent conversion of fibrinogen to fibrin; it accelerates inhibition of factors XII-a, XI-a, IX-a, and X-a.5 From a pathophysiological perspective, heparin blocks extension of thrombus and reduces the risk of emboli. The drug has a narrow therapeutic window and, in one study, was cited as the most common cause of drug-related deaths in the hospital.6 Significant bleeding occurs in about 7-30% of patients, and complications occur at the rate of 1-2% per day.6 The elderly patient and those taking aspirin are at greatest risk for hemorrhagic complications. Fortunately, for the patient and the emergency physician, complications rarely occur with the loading dose or during the first few hours. Thrombocytopenia develops in approximately 3% (reported range, 0.8-26.0%), usually, after 3-5 days.7 Heparin-induced thrombocytopenia usually is defined as a decrease in the platelet count below 150,000 per cubic millimeter that begins five or more days after the start of heparin therapy, in conjunction with a positive test for heparin-dependent IgG antibodies.8

Dosing. Dosing is important. Some studies suggest that, on occasion, clinicians may not give enough heparin, and, consequently, many patients are sub-therapeutic at 24 hours. This can be a serious concern, as delays in anticoagulation may lead to progressive or recurrent thromboembolism.9 In one study, more than 80% of patients who received heparin according to a weight-based nomogram had therapeutic heparin levels within 12 hours, compared with only 45% of standard (fixed) dose patients.10 A weight-based nomogram is most likely to achieve a rapid therapeutic response and may reduce the time required to achieve a therapeutic partial thromboplastin time (PTT) by half, as compared to fixed dosing.11 (See Table 2.) Measurement of the PTT is not necessary before beginning heparin.12

Table 2. Heparin Weight-based Nomogram
Initial dose = 80 U/kg bolus, 18 U/kg/h 
On repeat PTT in 6 hours:
PTT less than 40 s—rebolus with 80 U/kg, increase drip by 4 U/kg/h 
PTT 40-60 s—rebolus with 40 U/kg, increase drip by U/kg/h 
PTT 60-80 s—no change 
PTT 80-100 s—decrease drip by 2 U/kg/h 
PTT greater than 100—hold drip for 1 hour, then decrease drip by 3 U/kg/h 

Source: Pearson SD. A critical pathway to treat proximal lower-extremity deep vein thrombosis. Am J Med 1996;100:283-289. 
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The heparin drip must be continued for 4-5 days, possibly longer for patients with significant iliofemoral thrombosis. When IV heparin is used, the patient should be admitted to the hospital and the consultant should check the activated PTT in six hours. An adequate response is 1.5-2.5 times control.13,14 Absolute contraindications to heparin include active internal bleeding, malignant hypertension, CNS neoplasm, recent and significant trauma or surgery, and/or a history of heparin-induced thrombocytopenia. Relative contraindications include recent GI bleed or hemorrhagic stroke. Because heparin acts on antithrombin III, patients with antithrombin III deficiency are resistant to the drug. In this case, pretreat with antithrombin III concentrate or fresh frozen plasma to replenish this factor, and then begin standard heparin infusion.15

Warfarin (Coumadin)

After starting heparin or another anticoagulation agent (i.e., Low Molecular Weight Heparin [LMWH]) approved for DVT treatment, the emergency physician may order warfarin (Coumadin) 10 mg by mouth. By initiating warfarin on the first hospital day, the patient may be discharged in 4-5 days, by which time the INR will usually be in the 2.0-3.0 range.16 After discharge, most patients will require three months of anticoagulant therapy.17 Historically, there has been some controversy regarding the timing of warfarin therapy. The argument against starting warfarin in the emergency department (ED) is largely theoretical. If a patient has a protein C or S deficiency, if warfarin is given without heparin, it may have a procoagulant effect (accelerating pathological thrombosis). However, when heparin is started before warfarin, the patient will be therapeutically anticoagulated before the onset of any procoagulant effect from warfarin. Several authors have documented the safety of early warfarin administration.18-20 Most tellingly, the American College of Chest Physicians states that "the currently accepted approach is to begin heparin and oral anticoagulant therapy together at the time of diagnosis . . . "21

Hospital Therapy. Because of the cost associated with in-hospital treatment of DVT, critical pathways now emphasize outpatient managment when appropriate. There is considerable variation in the management of DVT, even within a single hospital, and clinical pathways may serve to decrease cost and length of stay.22

Clinical goals that can affect length of stay include the following:

    1.) Heparin bolus in ED using a weight based nomogram;
    2.) PTT > 60 within 12 hours of admission;
    3.) Oral dose of warfarin within 12 hours of therapeutic PTT (Many experts suggest warfarin be started orally at the same time heparin is given.);
    4.) Heparin for > 96 hours before DC;
    5.) INR of 2-3 no later than 120 hours after first dose of warfarin; and
    6.) Hospital DC within 12 hours of therapeutic INR.22

Low Molecular Weight Heparins (LMWH)

LMWH represents a major advance in the treatment of DVT, especially with the recent approval of the LMWH, enoxaparin, for treatment of DVT.23 Some studies that have compared standard intravenous unfractionated heparin (UH) to subcutaneous LMWH show that LMWH has improved antithrombotic effects and has fewer adverse consequences.24-26 In this regard, a meta-analysis study demonstrated that LMWH reduced thromboembolic complications, clinically important bleeding, and mortality when compared to unfractionated heparin.27 In addition, because LMWH can be given subcutaneously once or twice a day without need for coagulation tests, home treatment for DVT has become a clinical reality.

The LMWHs were first synthesized in the 1970s, and comprise a heterogeneous family of refined heparins with a molecular weight that ranges between 4000 and 9000 Daltons.28 This compares to the 12,000-15,000 Dalton molecular weight of unfractionated heparin. Because LMWH primarily inhibits factor X-a and has little effect on thrombin or platelet aggregation, there are fewer hemorrhagic complications.29 LMWH usually does not elevate the PTT. For this reason, LMWH is valued for its antithrombotic effect and lack of anticoagulant effect. There is evidence that suggests LMWHs administered subcutaneously in fixed doses adjusted for body weight and without laboratory monitoring may be more effective and safer than adjusted-dose standard heparin. In a major meta-analysis, LMWH reduced symptomatic thromboembolic complications by 53%, clinically important bleeding by 68%, and mortality by 47% when compared to standard heparin.30 A separate meta-analysis, including more than 2000 patients and 16 controlled trials, found that LMWH significantly reduced thrombus extension (odds ratio, 0.51) and demonstrated a trend toward decreased PE, fewer major bleeds, and lowered morality.26 Of particular concern to the internist, heparin-induced thrombocytopenia is less common with LMWH than with unfractionated heparin.31

The only LMWH currently approved for treatment of DVT in the United States is enoxaparin. The approved dose of enoxaparin for inpatient treatment of DVT, with or without PE is 1 mg/kg q 12 hours SQ or 1.5 mg/kg SQ qd. The dose of enoxaparin for outpatient therapy of deep venous thrombosis without pulmonary embolism is 1 mg/kg q 12 hours SQ.32,33

The safety and use of home treatment of DVT has undergone rigorous investigation. In two recent studies, authors compared adjusted-dose intravenous standard heparin administered in the hospital to fixed-dose subcutaneous LMWH administered twice daily at home.33,34 (See Table 3.) In both studies, home treatment with LMWH compared favorably with standard in-hospital therapy. Patients treated at home—or with a short hospitalization with early discharge to home—spent 67% less time in the hospital and had greater physical activity and social functioning than their standard heparin cohorts.34 Some patients had professional home health care assistance with their injectionsp; all had careful follow-up.

Table 3. Considerations in Home Treatment for DVT
Medical Exclusions
Concurrent Pulmonary Embolism (PE)
Serious co-morbid condition
Cancer, infection, stroke
Prior DVT or PE
Contraindications to anticoagulation
Familial bleeding disorder
Known deficiency of Antithrombin III, Protein C, Protein S
Pregnancy
Social Exclusions
No phone
Lives far from hospital
Unable to understand instructions or comply with follow-up
Family or patient resistance to home therapy
Mechanics and protocols
Subcutaneous enoxaparin 1 mg/kg q 12 hours for a minimum of five days and achieving INR of 2-3 (from warfarin therapy)
Warfarin to be started on first day of therapy
Need a mechanism to monitor INR during outpatient treatment
Close follow-up
Warn patients to return immediately for shortness of breath, hemorrhage, or clinical decomposition

Adapted from: Levine MN, et al. Ardeparin (low-molecular-weight heparin) vs graduated compression stockings for the prevention of venous thromboembolism. A randomized trial in patients undergoing knee surgery. Arch Intern Med 1996;156:851-856; Koopman MM, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996;334:682-687. 
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Pharmacoeconomic Considerations. With recent approval for DVT treatment, enoxaparin represents a breakthrough in out-of-hospital management of venous thromboembolic disease. It should be stressed that this approach is part of a larger movement to reduce total outcome costs. In a healthcare environment that puts a premium on effective therapy implemented in a cost-optimizing manner, outpatient DVT treatment with enoxaparin requires close examination.

Outcome Analysis and Implementation Strategies. Among the potential pharmacoeconomic advantages of out-of-hospital treatment with enoxaparin would be fewer admissions, increased patient comfort, and decreased overall costs. A disadvantage is that patients would have to be carefully evaluated to identify those who would be more safely treated in the hospital. In addition, much of the responsibility for treatment would be shifted from medical personnel to the patient and family, requiring self-administration of anticoagulants, self-monitoring for safety and efficacy, and compliance with clinic appointments for dosage adjustments of oral anticoagulants.

Home-Based Treatment of DVT: Maximixing Outcomes. As discussed, paradigm shifts in medication usage should be conservatively undertaken, as clinical experience helps to refine the management program. Initial treatment of DVT at home should follow a protocol in which all aspects of the treatment are clearly defined for the family and follow-up physician. Ideally, each ED should develop a treatment protocol that is written in advance by a team of medical professionals experienced in the treatment of DVT. The protocol should include criteria for patient selection, enoxaparin and warfarin therapy, patient and caregiver education, and monitoring. Each medical facility will need to develop a protocol that fits its own practice patterns.

One of the most important goals is developing criteria to identify patients who qualify for home-based treatment of DVT. As mentioned, most studies evaluating LMWH for outpatient therapy have excluded patients with a high risk of bleeding (malignant hypertension, peptic ulcer disease, recent surgery, known bleeding disorders, thrombocytopenia, high risk of falling), a high risk of recurrent thrombosis (previous CVT, pregnancy), and suspected PE. In addition, patients who resided a long distance from follow-up medical care, who were unable to care for themselves or did not have a competent caregiver in residence, and who were simply too ill to stay at home were not considered candidates from home-based treatment of DVT. Patients had to be willing to participate in their care, including self-administration of medications and follow-up for warfarin dosage adjustment when necessary. With these strict guidelines for patient selection, about 22-58% of patients screened in various studies were considered eligible for home-based treatment of DVT with a LMWH such as enoxaprin.32,35,36

Patient Instructions. Detailed instructions must be provided by the emergency medicine team. The patient or caregiver must be taught to administer the medication, monitor for adverse reactions and efficacy, and perform any other self-care deemed necessary (such as bed rest, leg elevation, and use of compression stockings). The patient or caregiver also must know what steps to take in the event of a complication. Instruction should begin immediately after diagnosis and can be provided by a nurse, a pharmacist, or both. Written instructions should also be provided.

Monitoring home-based treatment of DVT with LMWHs should include compliance, subcutaneous injection technique, local adverse effects from the injections, signs of bleeding, signs of recurrent thrombosis, and initiation and monitoring of warfarin therapy. Much of this monitoring can be done by the visiting nurse, who should see the patient daily during the initial treatment period of 5-9 days.

It may also be useful for a nurse, a pharmacist, or a physician from the treatment team to periodically telephone the patient or caregiver to ensure that treatment is going as planned and that there are no complications. For patients selected to undergo home-based treatment with enoxaparin, the LMWH should be administered for at least five days, and warfarin can be started on the same day as the LMWH or the day after. Blood should be drawn daily to monitor the prothrombin time for the first few days; the International Normalized Ration (INR) should be between 2.0 and 3.0 for two consecutive days before the LMWH is stopped.

Thrombolytic Agents

Thrombolytics are infrequently used for the treatment of DVT in the United States. In a survey of pulmonologists, only 28% had used thrombolytics for DVT.37 Streptokinase, given as a 24-72-hour continuous infusion, is the only FDA approved thrombolytic regimen for DVT.38 When compared to heparin, streptokinase produces more rapid resolution of symptoms and preserves venous valve integrity.39,40 There is weak evidence that thrombolytics may decrease the incidence of the postphlebitic syndrome.41 Despite these advantages, physicians are reluctant to use streptokinase for treatment of DVT because there is a three-fold risk of significant bleeding compared to heparin.37 Bleeding complications include major GI hemorrhage, as well as fatal and nonfatal CNS bleeds.42-44 There is a higher incidence of bleeding with the use of thrombolysis in DVT than in myocardial infarction. This may be related to the prolonged duration of therapy, as well as the higher incidence of comorbid illness with venous thrombosis.45 Urokinase, which had a small role in the treatment of DVT, has been removed from the market. Informed patients may not accept the increased risk of bleeding from streptokinase, despite a decreased risk of the postphlebitic syndrome.46 Patients given the choice would rather receive heparin, accepting the risk of post-phlebitic syndrome over that of major bleed. In general, the emergency physician should consider thrombolysis in cases of upper extremity DVT, and, perhaps, massive iliofemoral thrombosis. The best candidates are young, otherwise healthy patients with acute onset of severe symptoms and no contraindications to thrombolysis. Inform the patient of the increased risk of bleeding and potentially life-threatening complications associated with thrombolytics.

Special Management Issues

Phlegmasia Dolens. Phlegmasia alba dolens, the painful "milky white" leg occurs when a thrombosis obstructs venous outflow so completely that subcutaneous edema and blanching occur. As the condition worsens and obstruction becomes complete, capillary perfusion ceases and the limb becomes cyanotic; this condition is known as phlegmasia cerulean dolens (PCD). These patients may develop shock, gangrene, a pulmonary embolism, and go on to die.47 Such massive iliofemoral occlusion is a medical emergency that requires prompt intervention.48 Resuscitate the hypotensive patient with fluids, and if unresponsive to crystalloid infusions, begin vasopressor therapy with dopamine or norepinephrine. Anticoagulate such patients immediately, based on clinical presentation. Heparin or LMWH may prove sufficient in non-gangrenous forms, but the patient with PCD may require thrombolysis or surgical thrombectomy.49-51

Calf Thrombi. The management of venous thrombosis below the knee is controversial.52 Because many calf thrombi will propagate (32%) and subsequently embolize, some authorities suggest heparin or LMWH, admission, and initiation of warfarin.53 Others argue that because most calf thrombi will spontaneously resolve, anticoagulation is not necessary.54 However, patients who are not anticoagulated must undergo serial noninvasive studies to document clot regression.55 If serial plethysmography or ultrasound show progression, the patient should be anticoagulated. Because noninvasive studies such as ultrasound are less sensitive for distal than proximal thrombi, the emergency physician should schedule serial studies if they still suspect DVT despite a normal initial ultrasound.56 Alternatively, a negative, sensitive D-dimer study may obviate the need for serial studies, especially if the patient has few risk factors.57 The optimal number and timing of serial studies has not been clarified, but a negative study at one week generally is adequate to rule out clot progression.58

Upper Extremity DVT. Effort thrombosis usually occurs in physically active young males, and may lead to DVT of the upper extremity.59 Occasionally, a predisposing anatomic cause exists, such as cervical rib or thoracic outlet obstruction.60 Upper extremity DVT from central lines is observed in children. While it was once thought that upper extremity DVT was benign, clots from the upper extremities can cause significant or even fatal PE.61 Order duplex scanning to confirm the diagnosis.62 While heparin may be used, catheter-directed thrombolysis with urokinase was generally accepted as the treatment of choice for upper extremity DVT.59,60,63 However, no well-designed, controlled, randomized trials demonstrate the superiority of thrombolysis in this condition. Presumably, aggressive therapy will prevent the significant morbidity of recurrent hand and arm swelling. If patients have contraindications to thrombolysis or anticoagulation, placement of a Greenfield filter in the superior vena cava is recommended.

Pregnancy. Women are at increased risk of thrombosis throughout all stages of pregnancy. Prior to 20 weeks of gestation, duplex scanning is safe and accurate, but after 20 weeks, the gravid uterus presses on the inferior vena cava and confounds Doppler flow. An experienced sonographer can still detect clot within the vein by B-mode technology. In general, an indeterminate or non-diagnostic duplex scan in late pregnancy requires an additional study. MRI is an excellent choice, being both accurate and safe.64 Heparin, which does not cross the placenta, remains the treatment of choice for DVT in pregnancy. LMWH is generally considered safe in pregnancy and is rated category B. After initial intravenous anticoagulation, women with DVT should remain on daily subcutaneous heparin until delivery. Warfarin is contraindicated during pregnancy due to its teratogenic effects,65 but it should be started postpartum if the patient does not breast-feed.

Suspected Acute vs. Chronic DVT. Some patients with prior DVT who have recurrent symptoms require a specialized work-up.66,67 However, even in these patients, Duplex scanning remains the initial imaging study of choice.68 If the study is normal, DVT is unlikely. A scan that clearly demonstrates fresh clot, based on homogeneity and echogenicity, is confirmatory of acute DVT; however, many studies will be equivocal. Patients with DVT can demonstrate persistent abnormalities on ultrasonography months to years after the acute event; in fact, 80% of ultrasounds are abnormal at three months and 50% abnormal at one year.69 Comparison with a prior duplex scan will differentiate new vs. old changes, but access to a previous scan is oftentimes impossible. A combination of clinical suspicion, D-dimer testing, serial venous ultrasonography, lung scanning, fibrinogen leg scanning, or nuclear magnetic imaging may differentiate between old and new deep venous thrombosis.68

Patients with DVT while on Warfarin. If a patient on warfarin develops DVT, the emergency physician must decide if the patient is adequately anticoagulated, which is defined as an INR between 2.0 and 3.0. If the INR is below 2.0, start heparin and increase the daily dose of warfarin. If the INR is greater than 2.0, begin heparin and obtain consultation regarding vena cava filter placement. Most authorities believe that these patients require a filter to prevent PE.70 A minority opinion recommends heparin and the addition of antiplatelet drug, such as dipyridamole 75 mg by mouth three times a day in addition to the warfarin regimen.71,72

Superficial Thrombophlebitis. Superficial thrombophlebitis may propagate into the deep system. Simple, localized phlebitis, which develops at the site of a recent IV catheter, is generally benign. The emergency physician should order a duplex scan if the patient has involvement of the saphenous vein or significant risk factors for DVT.73,74 Treat isolated superficial involvement with compression bandages and nonsteroidal anti-inflammatory drugs.75 While some authorities recommend venous excision and local thrombectomy,76 less drastic measures usually suffice. If the patient is an intravenous drug user or is toxic appearing, consider septic thrombophlebitis, and admit for broad-spectrum antibiotics.

Summary

The patient with a painful or swollen leg presents a diagnostic challenge for the emergency physician. (See Table 4 and Figure 1.) Because of the limitations of physical examination, objective imaging studies are necessary for the majority of patients with unexplained limb complaints. Duplex scanning remains the diagnostic study of choice to evaluate for DVT. The red cell agglutination test of D-dimer is very sensitive for thrombosis, and a negative test makes proximal clot unlikely. Recognition of alternative conditions, such as compartment syndrome, septic arthritis, and cellulitis, is essential for optimal care. A weight-based nomogram is the best means to administer heparin, and ED use of warfarin can decrease hospital stay. Recognize atypical presentations of PE and phlegmasia dolens to institute lifesaving interventions. The use of subcutaneous LMWH is safe and effective and permits home treatment of DVT. Enoxaparin has approval for treatment of DVT, and outpatient management of carefully selected patients will become the standard of care.

Table 4. Pitfalls in the Management of Deep Venous Thrombosis
1. Relying on calf measurements and negative Homans signs to rule out DVT 
2. Failure to perform objective testings on patients with presumed cullulitis of the leg 
3. Failure to evaluate deep system in patients with superficial thrombophlebitis 
4. Failure to consider the clinical likellihood of DVT when interpreting Doppler studies 
5. Failure to use a weight-based nomogram to dose heparin 
6. Failure to either anticoagulate or perform serial studies on patients with isolated calf vein thrombosis 
7. Failure to perform a simple screen for malignancy in patients with unexplained deep venous thrombosis
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