Venous Thromboembolism (VTE)

Diagnosis & Treatment Guideline

Diagnosis of Deep Venous Thrombosis (DVT) Wells Prediction Rules Recommended Tests Diagnosis of Pulmonary Embolism (PE) Wells Prediction Rules PERC Rule Recommended Tests Recommended Test for Pregnant Patients Treatment for DVT & PE Goals Pharmacologic Options Treatment Settings Follow-up/Monitoring Evidence/References Clinician Lead and Guideline Development Most recent comprehensive literature review: December 2010

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Guidelines are systematically developed statements to assist patients and providers in choosing appropriate health care for specific clinical conditions. While guidelines are useful aids to assist providers in determining appropriate practices for many patients with specific clinical problems or prevention issues, guidelines are not meant to replace the clinical judgment of the individual provider or establish a standard of care. The recommendations contained in the guidelines may not be appropriate for use in all circumstances. The inclusion of a recommendation in a guideline does not imply coverage. A decision to adopt any particular recommendation must be made by the provider in light of the circumstances presented by the individual patient.

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline Copyright 19972011 Group Health Cooperative. All rights reserved.

Diagnosis of Deep Venous Thrombosis (DVT)

Step 1. Determine pretest probability of DVT using Wells prediction rules. Step 2. Order indicated tests depending on pretest probability.

Wells Prediction Rules

Table 1. Wells prediction rules for diagnosing DVT 1,2 Clinical characteristic Active cancer (treatment ongoing, within previous 6 months, or palliative) Paralysis, paresis, or recent plaster immobilization of the lower extremities Recently bedridden > 3 days or major surgery within 12 weeks requiring general or regional anesthesia Localized tenderness along the distribution of the deep venous system Entire leg swollen Calf swelling 3 cm larger than the asymptomatic side (measured 10 cm below tibial tuberosity) Pitting edema confined to the symptomatic leg Collateral superficial veins (non-varicose) Alternative diagnosis at least as likely as deep venous thrombosis
1 2 3 3

Score (if yes) +1 +1 +1 +1 +1 +1 +1 +1 -2

Wells et al 1997. The Wells criteria are available online at: http://www.mdcalc.com/wells-criteria-for-dvt. In patients with symptoms in both legs, use the more symptomatic leg. An alternative diagnosis may include: superficial phlebitis, postphlebitic syndrome, cellulitis, muscle strain or tear, leg swelling in paralyzed limb, venous insufficiency, edema due to systemic cause such as CHF or cirrhosis, external venous obstruction (e.g., due to tumor), lymphangitis or lymphedema, popliteal (Bakers) cyst, hematoma, pseudoaneurysm, or knee abnormality.

Table 2. Interpreting Wells prediction rules for DVT Test Wells prediction rule for diagnosing DVT Results >3 12 <0 Interpretation High pretest probability of DVT Intermediate pretest probability of DVT Low pretest probability of DVT

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

Recommended Tests
Table 3. Recommended test for evaluating suspected DVT in patients with intermediate or high pretest probability (Wells score > 1) Test Ultrasound
1,2

Results Positive Negative

Next steps Initiate treatment. (See Table 12 for treatment recommendations.) Consider a D-dimer (if not already done) if there is high degree of clinical suspicion. If D-dimer is positive, order a second ultrasound in 37 days. If still suspected, order an MR venogram.

1 2

Ultrasound is less sensitive for diagnosing DVT limited to the calf than it is for diagnosing DVT in proximal veins. Contrast venography is considered the definitive test to rule out the diagnosis of DVT; however, use contrast venography sparingly due to the morbidity associated with the procedure.

Table 4. Recommended test for evaluating suspected DVT in patients with low pretest probability (Wells score < 1) Test Interpretation Result / facility Reference ranges vary by specific test and location AMB, BVU, CH EVT All other locations OLY, SIL, TCS (Providence (GH labs) Hospital lab) > 400 ng/mL > 0.49 ug/mL Consult the facilitys reference range. Consult the facilitys reference range. Next steps

Positive D-dimer 13 Negative

1 2

Perform duplex ultrasound with compression. Consider alternative diagnosis.

400 ng/mL

0.49 ug/mL

This test should be performed on a STAT ("patient waiting") basis. For patients with reliable follow-up, primary care clinicians may consider ordering a routine D-dimer test if the primary care physician can review the results the same day and refer the patient to urgent care for further evaluation if indicated. The PCP should contact the urgent care provider to discuss the patient and disposition plan. This step is important for patient safety and quality of care. False positive D-dimer results may be found in the following circumstances: Age (> 50 years) Heart disease Liver disease Pregnant women Immobility Recent surgery Active malignancy Trauma Prolonged/permanent immobility Infection Sickle cell disease Disseminated intravascular coagulation (DIC)

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

Diagnosis of Pulmonary Embolism (PE)

Step 1. Step 2. Step 3. Determine pretest probability of PE using Wells prediction rules. For patients with a low pretest probability based on the Wells prediction rules, assess risk using the Pulmonary Embolism Rule-out Criteria (PERC). Order indicated tests depending on pretest probability and PERC results.

Wells Prediction Rules

Table 5. Wells prediction rules for diagnosing PE 1 Clinical characteristic Previous pulmonary embolism or deep vein thrombosis Heart rate > 100 beats per minute Recent surgery or immobilization Clinical signs of deep vein thrombosis Alternative diagnosis less likely than pulmonary embolism (e.g., myocardial infarction, pericarditis, pneumonia, pneumothorax, chest wall pain, congestive heart failure, pleuritis, pericardial tamponade) Hemoptysis Cancer (treatment ongoing, within previous 6 months, or palliative)
1

Score (if yes) +1.5 +1.5 +1.5 +3 +3

+1 +1

Chagnon et al 2002. The Wells criteria are available online at: http://www.mdcalc.com/wells-criteria-for-pulmonary-embolism-pe.

Table 6. Interpreting Wells prediction rules for PE Test Wells prediction rule for diagnosing PE Results >7 26 01 Interpretation High pretest probability Intermediate pretest probability Low pretest probability

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

PERC Rule
Table 7. PERC rule for assessing PE risk 1,2 Clinical characteristic Age < 50 years Heart rate < 100 beats per minute O2 sat on room air > 94% No prior history of DVT or PE No recent trauma or surgery No hemoptysis No exogenous estrogen No clinical signs suggesting DVT
1

Meets criteria (yes/no)

PERC (Kline et al 2004; Kline et al 2008) is a validated rule with high sensitivity and negative predictive value; however, it has a low specificity, which tends to increase as the risk of PE in the population decreases. This indicates that the test would be more applicable for low-risk and very low-risk PE patients rather than the general ER population. The PERC rule should not be applied alone but in combination with the clinicians judgment. The PERC rule is available online at: http://www.mdcalc.com/perc-rule-for-pulmonary-embolism.

Table 8. Interpreting PERC rule for PE Test PERC rule Results Patient does not meet all eight criteria. Patient does meet all eight criteria. Interpretation The PERC rule only applies if all eight criteria are met. According to the PERC study, there is less than 2% risk of PE in this patient.

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

Recommended Tests
Table 9. Recommended tests for evaluating suspected PE in patients with intermediate or high pretest probability (Wells score > 2) 1 Test CT pulmonary angiography 2,3 Results Positive Next steps Initiate treatment. (See Table 12 for treatment recommendations.) Review pretest probability and consider a D-dimer (if not already done). PE less likely with positive D-dimer Consider alternative diagnosis. 4 Results Next steps

Negative

PE likely with negative Perform duplex ultrasound (with compression) of the D-dimer leg. 5 PE likely with positive D-dimer

Consider initiating treatment if PE is suspected but diagnostic testing will not be completed within a reasonable timeframe of roughly 4 hours or at clinical discretion. CT pulmonary angiography is the preferred initial screening in patients with normal renal function and no contrast allergy. Ventilation/perfusion (V/Q) lung scan is indicated for patients with poor renal function (estimated glomerular filtration 2 rate [eGFR] < 30 mL/min/1.73 m or creatinine clearance < 30 mL/min). Risk of PE is very low. Further testing for PE is not indicated unless high clinical suspicion continues or discordant objective findings (ICSI 2010). If positive, initiate treatment for VTE. If negative, risk of PE is very low. Further testing for PE is not indicated unless high clinical suspicion continues or discordant objective findings are encountered (ICSI 2010).

Table 10. Recommended tests for evaluating suspected PE in patients with low pretest probability (Wells score < 1) and who do not meet all PERC rule criteria 1 Test Interpretation Result / Facility Reference ranges vary by specific test and location AMB, BVU, CH EVT All other locations OLY, SIL, TCS (Providence (GH labs) Hospital lab) > 400 ng/mL 400 ng/mL > 0.49 ug/mL 0.49 ug/mL Consult the facilitys reference range. Consult the facilitys reference range. Next steps

Positive D-dimer 24 Negative

1

Perform CT pulmonary angiography. 5 Consider alternative diagnosis.

No further evaluation is necessary if the patient is younger than 50 years, has no comorbidities, and reports a short duration of symptoms. This test should be performed on a STAT ("patient waiting") basis. For patients with reliable follow-up, primary care clinicians (PCP) may consider ordering a routine D-dimer test if the PCP can review the results the same day and refer the patient to urgent care for further evaluation if indicated. The PCP should contact the urgent care provider to discuss the patient and disposition plans. This step is important for patient safety and quality of care. False positive D-dimer results may be found in the following circumstances: Age (> 50) Pregnant women Active malignancy Heart disease Immobility Trauma Liver disease Recent surgery Prolonged/permanent immobility Infection Sickle cell disease Disseminated intravascular coagulation (DIC)

2 3

Ventilation/perfusion (V/Q) lung scan is indicated for patients with poor renal function (estimated glomerular filtration 2 rate [eGFR] < 30 mL/min/1.73 m or creatinine clearance < 30 mL/min). 6

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

Recommended Tests for Pregnant Patients

Table 11. Recommended tests for evaluating suspected PE in pregnant patients Test D-dimer
1

Results > 400 ng/mL in GH labs

Next steps

Results of ultrasound Positive

Next steps Initiate treatment. (See Table 12 for treatment recommendations.) Thoracic imaging is indicated. 24

Perform duplex ultrasound or (with compression) > 0.49 ug/mL in EVT and of the leg. some outside labs 400ng/mL in GH labs or 0.49 ug/mL in EVT and some outside labs Consider alternative diagnosis.

Negative

A normal D-dimer level has the same exclusion value for PE in pregnant women as in other patients with suspected PE and it is recommend that it be measured even though the probability of a negative test is lower than in nonpregnant patients (Torbicki 2008). Chest X-ray can be performed safely in the first and second trimesters. Women with clinical suspicion of PE and a normal chest X-ray are more likely to achieve a diagnosis from a ventilation perfusion scan vs. CT angiography. CT was a better initial test for patients with an abnormal chest X-ray (Cahill 2009). CT angiogram gives a lower dose of radiation to the fetus even in the third trimester than ventilation/perfusion (V/Q) scan. Use of breast shields to decrease the radiation exposure of the womans breast by 5080% is recommended. A V/Q lung scan would give a lower dose of radiation to the breast but more to the fetus. V/Q lung scan is indicated for patients with poor renal function (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2 or creatinine clearance < 30 mL/min).

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

Treatment of DVT & PE

Goals
The goals of deep vein thrombosis treatment are to prevent clot from increasing in size, reduce the risk of pulmonary embolism, and to prevent deep vein thrombosis from recurring. The goals of pulmonary embolism treatment are to prevent clot from increasing in size, reduce morbidity and mortality, and to prevent recurrence of venous thromboembolism.

Treatment Approaches
Mechanical methods of DVT treatment are used in patients who are at high risk of bleeding and cannot be given medications, or as an adjunct to anticoagulation-based medications. Anticoagulation medications are used in patients who do not have contraindications.

Pharmacologic Options
Table 12. Pharmacologic treatment options for patients diagnosed with DVT or PE Eligible population Line Pharmacologic method Duration of treatment LMWH, UFH, or fondaparinux Patients with DVT or PE not at increased risk for bleeding 2,3 1st Minimum of 5 days LMWH 47 Enoxaparin (1.5 mg/kg every 24 and hours or 1 mg/kg every 12 hours) or dalteparin (NF) 200 IU/kg/d Until two consecutive INR test results are and between 2.03.0. Warfarin PO 8 Heparin (IV unfractionated heparin) 4,5 80 u/kg bolus followed by 18 u/kg/hr infusion and Warfarin PO 8 3rd Fondaparinux 6 (PA) < 50 kg: 5 mg once daily 50100 kg: 7.5 mg once daily > 100 kg: 10 mg once daily and Warfarin PO 8
[Table 12. footnotes found on the following page]

Warfarin 1 36 months for first event and then reevaluate to determine risk of repeat embolus and need for ongoing treatment. For second event, continue treatment indefinitely.

2nd

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

[Table 12. footnotes from the previous page]

1 2

See Table 12b for more specific recommendations regarding duration of warfarin treatment. See Table 12a, risk factors for bleeding. Reassess risks of bleeding and VTE within 24 hours of admission and whenever the clinical situation changes. Consult pulmonology regarding patients with complicated DVT/PE who may require alternative therapies (e.g., thrombolytic therapy, surgical thrombectomy). LMWH is superior to unfractionated heparin for the initial treatment of DVT/PE, particularly for reducing mortality and reducing the risk for major bleeding during initial therapy. IV unfractionated heparin is preferred over LMWH in patients with massive PE, in patients for whom thrombolytic therapy is being considered or planned, or in situations where there is a concern about subcutaneous absorption. Do not use LMWH or fondaparinux in patients with renal failure (estimated glomerular filtration rate [eGFR] < 30 2 mL/min/1.73 m or creatinine clearance < 30 mL/min). If patient has malignancy or BMI > 35, then dose enoxaparin at 1 mg/kq every 12 hours. The initial dose of warfarin should be 5 mg in patients who are likely to highly sensitive, including those with: malnutrition, malabsorption, decompensated CHF, postoperative major non-cardiac surgery (NPO > 3 days), chronic liver disease, known malignancy, baseline INR > 1.4, and those taking the following medications: amiodarone, fluconazole, metronidazole, propafenone, quinolones, or sulfa-containing medications. When practical, start warfarin on day 1.

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Table 12a. Bleeding risk factors 1 Active bleeding Acquired bleeding disorder (e.g., liver failure) Thrombocytopenia (platelets < 75 x 10^9/l) Lumbar puncture/epidural/spinal anesthesia within the previous 4 hours or expected within the next 12 hours
1

Acute stroke Current use of anticoagulants Uncontrolled systolic hypertension ( 230/120 mm Hg) Untreated inherited bleeding disorders (such as hemophilia or von Willebrand disease)

Based on the NICE clinical guideline (2010).

Table 12b. Duration of treatment for patients with DVT or PE Condition First episode of idiopathic/unprovoked PE or proximal/distal DVT 1 Duration of treatment Continue treatment for at least 3 months then reevaluate the risks and benefits of long-term therapy. Factors to consider include:
(Expert opinion)

Recurrent idiopathic/unprovoked DVT/PE DVT/PE and cancer

1

Patient lifestyle Ease of maintaining therapeutic INR Characteristics of embolus D-dimer level after 36 months of treatment Ultrasound findings after 36 months of treatment

Continue treatment indefinitely. Continue LMWH for the first 36 months, followed by LMWH or warfarin indefinitely or until cancer is resolved.

DVT/PE secondary to transient risk factors Continue treatment for 3 months.

Including symptomatic DVT below the knee.

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

Table 13. Pharmacologic treatment options for pregnant patients receiving anticoagulation Eligible population Pregnant patients Pharmacologic method 1 LMWH Enoxaparin 1 mg/kg every 12 hours or dalteparin (NF) 200 IU/kg/d or Heparin (IV unfractionated heparin) 80 u/kg bolus followed by 18u/kg/hr infusion
1

Duration of treatment (LMWH or UFH) Continue treatment throughout pregnancy and 6 weeks postpartum.

Discontinue treatment at least 24 hours prior to elective induction of labor.

Warfarin is contraindicated in pregnancy due to adverse effects on the fetus.

Treatment Setting (Inpatient vs. Outpatient)

Outpatient treatment of DVT with LMWH is safe and cost-effective for carefully selected patients, and should be considered if the required support services are in place. Outpatient treatment of PE with LMWH is safe and cost-effective for carefully selected patients, and should be considered after a brief inpatient stay to stabilize the patient if the required support services are in place. Most studies of outpatient treatment excluded patients with previous VTE, thrombophilic conditions, significant comorbid illnesses, pregnant patients, and those unlikely to adhere to outpatient therapy; therefore, this recommendation cannot be generally applied to these groups.

Follow-up/Monitoring for DVT & PE

Table 14. Recommendations for testing prior to initiating treatment Test(s) Complete blood count (Hemoglobin/hematocrit, platelets, and white blood cell [WBC]) Condition/complication Myeloproliferative disorder (e.g., polycythemia vera, essential thrombocythemia) Interpretation/next steps Elevations in hematocrit or platelet count, especially in patients with splenomegaly, should lead to consideration of myeloproliferative disorders. These disorders predispose patients to venous and arterial thrombotic events, particularly when the abnormalities are not controlled by therapy. Secondary polycythemia or reactive thrombocytosis may suggest underlying malignancy. Anemia, leukopenia, and thrombocytopenia are often found in paroxysmal nocturnal hemoglobinuria. If PTT results are abnormal, screen for antiphospholipid antibodies (e.g., anticardiolipin antibody and lupus anticoagulant). Do not use LMWH or fondaparinux in patients with renal failure (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2 or creatinine clearance < 30 mL/min).

Occult neoplasm Paroxysmal nocturnal hemoglobinuria Partial thromboplastin time (PTT) Creatinine/eGFR Antiphospholipid syndrome

Chronic kidney disease

Prothrombin time/ international normalized ratio (PT/INR)

(Purpose is to establish baseline before initiating anticoagulation.)

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

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Table 15. Recommendations for medication monitoring of patients currently receiving VTE treatment Anticoagulation therapy LMWH Test(s) Platelet count Xa Frequency 1 Condition/complication Interpretation/next steps Stop LMWH; consider direct thrombin inhibitor treatment.

Every 35 days for 2 Thrombocytopenia weeks, then weekly until 1 week after the last dose. If obese (BMI > 40) or with renal failure on day 35 of therapy, then on day 10 of therapy, then monitor monthly. Every 35 days for 2 Heparin-induced weeks, then weekly until 1 Thrombocytopenia (HIT) 2 week after the last dose. Every 24 days until INR is in range for 23 consecutive measurements, then repeat in 2 weeks. Warfarin-induced hypercoagulation or Hypocoagulation

Heparin

Platelet count INR

Stop heparin; consider direct thrombin inhibitor treatment. Adjust dose per warfarin dosing calculator.

Warfarin

See the list of medications that interact with warfarin: http://incontext.ghc.org/rx/med/documents/top20_warfarininteractions.pdf Manifested by a 50% or greater platelet count drop 514 days after starting a course of heparin. If HIT is suspected, referral to a hematologist or thrombosis specialist is recommended.

Table 15a. Recommendations for condition/complication monitoring of patients currently receiving VTE treatment Condition/complication Post thrombotic syndrome
1

Test(s) Monitor for chronic leg pain, fullness, swelling, heaviness.

Interpretation/next steps Knee-length graduated elastic compression stockings (3040 mm Hg) 2 or Intermittent pneumatic compression

Frequency/duration Starting within 1 month of diagnosis, wear on the affected leg in the daytime for 2 years.

Persistent DVT
1 2 3 4

Repeat ultrasound. 3,4

Consult with hematology if evidence of residual clot.

The American College of Chest Physicians (ACCP) recommends this surveillance strategy. Appropriate for patients without venous leg ulcers. If symptoms are still present at the end of the treatment, consider a repeat ultrasound. The presence of residual venous clot at three months has been associated with a high risk of recurrent VTE if anticoagulation is stopped, 23.1% compared to 1.3% in those without residual clot (Siragusa 2008).

Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline

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Table 16. Testing to consider in patients with suspected thrombophilia Eligible population 1 Patients with a recurrent idiopathic thrombosis (more than one event) Test(s) 2 All: Factor V Leiden Factor II mutation Protein C and S Lupus anticoagulant Antithrombin III

Patients with an unprovoked event: Age < 50 years or With a family history of VTE among one or more first-degree relatives Patients with a massive VTE or VTE in unusual location (portal, hepatic, mesenteric, or cerebral vein)
1 2

All the above

All the above and: JAK2 mutation

Consider consult with hematology for patients with any of these risk factors. This testing should be done 34 weeks after discontinuation of anticoagulant.

Evidence/References
Group Health adapted the recommendations of the American College of Chest Physicians (ACCP) and the Institute for Clinical Systems Improvement (ICSI) for the diagnosis and treatment of venous thromboembolism (VTE); references to these sources are listed below. Hirsh J, Guyatt G, Albers G, Harrington R, Schnemann H. Antithrombotic and thrombolytic therapy: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:71S109S. Available online at: http://chestjournal.chestpubs.org/content/133/6_suppl/71S.full.html. Institute for Clinical Systems Improvement (ICSI). Venous thromboembolism diagnosis and treatment guideline (10th edition). March 2010. Available online at: http://www.icsi.org/guidelines_and_more/gl_os_prot/cardiovascular/venous_thromboembolism/venous_th romboembolism_6.html.

Clinician Lead and Guideline Development

Clinician Lead, Clinical Improvement & Prevention
Michelle Seelig, MD, Family Medicine Medical Director of Clinical Knowledge & Support Contact: 206-326-3938

Last Update
Most recent comprehensive literature review: December 2010

Process of Development
This guideline was adapted from externally developed evidence-based guidelines and organizations that establish the community standards for the prevention of venous thromboembolism. External sources of recommendations include the American College of Chest Physicians (ACCP) and the Institute for Clinical Systems Improvement (ICSI). The following specialties were represented on the development team: epidemiology, family medicine, pharmacy, internal medicine, orthopedics, hematology/oncology, and urgent care.
Venous Thromboembolism (VTE) Diagnosis & Treatment Guideline 12