Venous Thromboembolism - Management Management

Evaluation

Clinical Evaluation

A reasonable clinical suspicion is required to avoid missing the diagnosis of pulmonary embolism. Evaluating the likelihood of pulmonary embolism in an individual patient according to the clinical presentation is of utmost importance in the interpretation of diagnostic test results and the selection of an appropriate diagnostic strategy. A bedside transthoracic echocardiogram may be done in patients who are hemodynamically unstable to differentiate suspected high-risk pulmonary embolism from other acute life-threatening conditions. Patients should also be evaluated for risk factors for venous thromboembolism.

It is recommended to perform initial risk stratification in hemodynamically unstable patients with suspected or confirmed pulmonary embolism to identify those with a high risk of early mortality. Acute pulmonary embolism severity may be stratified using validated scores from combined clinical, laboratory, and imaging prognostic factors in patients who are hemodynamically stable. The Pulmonary Embolism Severity Index (PESI) identifies the patient's overall mortality risk using pulmonary embolism severity and comorbidity. A score of ≥1 indicates a 30-day mortality risk of 10.9% in the simplified version of PESI.

Absolute Contraindications to Thrombolysis

The following are absolute contraindications to thrombolysis: 

• Hemorrhagic stroke or stroke of unknown origin at any time
• Major trauma, surgery, or head injury in the past 3 weeks
• Ischemic stroke within the past 6 months
• Central nervous system (CNS) damage or tumors
• Severe coagulation disorders
• Active bleeding
• Known increased risk for bleeding (bleeding diathesis)

Relative Contraindications to Thrombolysis 

The following are relative contraindications to thrombolysis:

• Transient ischemic attack within the past 6 months
• Puncture of a non-compressible vessel
• Uncontrolled severe hypertension (systolic blood pressure of >180 mmHg, diastolic blood pressure [DBP] of >100 mmHg)
• Neurosurgery or ophthalmologic surgery within the last 1 month
• Ischemic stroke within the last 2 months
• Gastrointestinal bleeding within the last 10 days
• Active peptic ulcer disease
• Recent traumatic cardiopulmonary resuscitation (CPR)
• Pregnancy or within 1 week postpartum 
• Infective endocarditis
• Oral anticoagulant therapy
• Advanced liver disease

Prompt Management of Clinical Instability

Oxygen (O2) Supplementation  

Oxygen supplementation may be necessary in patients with hypoxemia. Hypoxemia can usually be reversed with nasal oxygen so mechanical ventilation is rarely necessary.  

Mechanical Ventilation  

Mechanical ventilation may be needed temporarily in patients who appear toxic and hypoxic. Care should be taken to limit its hemodynamic adverse effects. Positive intrathoracic pressures induced by mechanical ventilation may reduce venous return and worsen right ventricular failure. Low tidal volumes of approximately 6 mL/kg body weight are recommended.  

Hemodynamic Support  

Fluid Loading  

Fluids may be administered initially and cautiously, but other vasoactive therapies should promptly follow. The usefulness of fluid challenge is controversial and should not exceed 500 mL over 15 to 30 minutes. It may be harmful when systemic hypotension is present.  

Adrenergic Agonists  

Adrenergic agonists should be considered for patients with low cardiac index and normal blood pressure or with impending hypotension. In high-risk pulmonary embolism patients, Dobutamine and/or Norepinephrine should be considered.  

Please see Adrenergic Agonists under Pharmacological Therapy: Prompt Management of Clinical Instability for further information.  

Nitric Oxide Inhalation  

Nitric oxide inhalation may be indicated in patients with pulmonary hypertension and a patent foramen ovale. It may improve the hemodynamic status and gas exchange in patients with pulmonary embolism.

Principles of therapy

Phases of Anticoagulation in Deep Vein Thrombosis  

The initial treatment phase is given up to 10 days with the aim of rapidly initiating anticoagulation to prevent the progression of deep vein thrombosis and pulmonary embolism.  

The principal treatment phase is given during the first 3 months to maintain therapeutic levels of anticoagulation to prevent deep vein thrombosis progression and pulmonary embolism and reduce the risk of early recurrent venous thromboembolism. Anticoagulation for 3 months is recommended in patients with provoked proximal deep vein thrombosis with a major transient risk factor.  

The extended treatment phase after 3 months of primary treatment is given to reduce the long-term risk of recurrent venous thromboembolism. It is recommended for patients with second or subsequent unprovoked deep vein thrombosis. Indefinite anticoagulation is recommended in patients with a high risk of recurrence unless the patient is with a high risk of bleeding, including patients with active cancer or persistent major risk factors (eg rheumatic disorder, severe thrombophilia). Extended anticoagulation is recommended in patients with a medium risk of recurrence which includes patients with recurrent venous thromboembolism, unprovoked event, minor, soft transient risk factors (eg travel), obesity, heart failure, chronic obstructive pulmonary disease (COPD), and male gender.   

General Therapy Principles Regarding Heparin  

Anticoagulation should be administered without delay in patients with intermediate or high clinical probability of pulmonary embolism during diagnostic workup and in low probability patients once pulmonary embolism is confirmed.   

If pulmonary embolism occurs postoperatively, Heparin therapy should be started after consultation with the surgeon and at 12 to 24 hours after major surgery. Treatment could be delayed even longer if there is any evidence of bleeding from the surgical site.  

Similar initial and long-term treatment is recommended for asymptomatic deep vein thrombosis.  Protamine sulfate may be used for the reversal of anticoagulation.

General Therapy Principles Regarding Anticoagulant Therapy

For patients with deep vein thrombosis or pulmonary embolism, the primary treatment of 3 months duration is recommended: 

• Proximal deep vein thrombosis or pulmonary embolism provoked by major surgery or trauma that is transient: Treatment is stopped after 3 months
• Proximal deep vein thrombosis or pulmonary embolism which is unprovoked or associated with a non-surgical transient risk factor: Treat for 3 to 6 months 
• Proximal deep vein thrombosis or pulmonary embolism which is recurrent unprovoked, provoked by active cancer or antiphospholipid antibody syndrome or by a chronic risk factor: Treat with extended anticoagulation 
• Distal deep vein thrombosis provoked by a transient risk factor: Treat for 6 weeks
• Distal deep vein thrombosis which is unprovoked or with persisting risk factors: Treatment is stopped after 3 months

Thrombus Removal  

Early thrombus removal strategies may be considered in patients with symptomatic iliofemoral deep vein thrombosis.  

Thrombolysis in Massive or Sub-Massive Pulmonary Embolism  

High-risk pulmonary embolism patients are recommended to receive systemic thrombolytic therapy. Patients with hemodynamic deterioration on anticoagulation therapy are recommended to undergo rescue thrombolytic treatment. Studies have shown a more rapid improvement in radiographic and hemodynamic abnormalities in acute massive pulmonary embolism patients who received thrombolytic agents followed by anticoagulant agents over conventional anticoagulant agents alone. There were no clinically relevant outcomes for death rate or for the resolution of symptoms.  

Treatment started within 48 hours of symptom onset provides the most benefit, though thrombolysis can still be used in those who are symptomatic for 6 to 14 days. Catheter-directed thrombolytic therapy may also be considered in patients with massive iliofemoral deep vein thrombosis (weigh risk vs benefit) with symptoms of <14 days, limb-threatening deep vein thrombosis (phlegmasia cerulea dolens), good functional status, low risk of bleeding, and ≥1-year life expectancy.  

Massive Pulmonary Embolism  

The use of thrombolytic therapy in pulmonary embolism should be individualized. Patients with hemodynamically unstable pulmonary embolism who are at low risk of bleeding are the most appropriate candidates.  

Thrombolytic therapy may also be considered in patients with compromised oxygenation; free-floating right ventricular thrombus or patent foramen ovale documented by echocardiography; and massive hemodynamically significant pulmonary embolism without systemic hypotension or profound hypoxemia.  

Sub-massive Pulmonary Embolism  

The use of thrombolytics in patients with sub-massive pulmonary embolism (hemodynamically stable patients with echocardiographic and/or biomarker evidence of right ventricular dysfunction) is controversial. Further studies are needed to show a clinically relevant improvement in the benefit-risk ratio of thrombolytic treatment over traditional anticoagulant therapy in these patients.  

Thrombolysis may be reasonably considered in select younger patients with sub-massive pulmonary embolism at low bleeding risk or for those with high decompensation risk because of concomitant cardiopulmonary disease.  

Please see Thrombolytic Agents under Pharmacological Therapy: Thrombolysis in Massive or Sub-massive Pulmonary Embolism for further information.

Pharmacological therapy

Parenteral Anticoagulants in the Management of Deep Vein Thrombosis and Non-massive Pulmonary Embolism

Unfractionated Heparin (UFH) and Low-Molecular-Weight Heparin (LMWH)  

Both subcutaneous LMWH and intravenous UFH short-course treatments are recommended for objectively confirmed non-massive pulmonary embolism. Either LMWH or UFH is appropriate for the initial treatment of pulmonary embolism. It is not recommended to give UFH or LMWH monotherapy in patients with severe renal impairment (Creatinine Clearance [CrCl] of <30 mL/min).  

UFH  

Intravenous UFH treatment in pulmonary embolism is well-established. UFH should be considered as a first-dose bolus; for massive or sub-massive pulmonary embolism; without delay in suspected high-risk pulmonary embolism patients with hemodynamic instability; and when rapid reversal of effect may be required.  

It may also be given to patients with high bleeding risks, receiving thrombolysis, or undergoing invasive procedures. It is used for the initial management of patients with phlegmasia cerulea dolens delivered in combination with aggressive leg elevation and fluid resuscitation. Patients with confirmed pulmonary embolism and hemodynamic instability may be given continuous UFH infusion with thrombolytic therapy. UFH is preferred over LMWH in patients with severe renal failure.  

Intravenous UFH has been proven effective in the therapy of pulmonary embolism and deep vein thrombosis. Studies have shown a reduced mortality rate when UFH has been used to treat venous thromboembolism disease. The recurrence of venous thromboembolism is unusual when UFH is infused at a rate that prolongs the aPTT >1.5-2.5 times the control value and when adequate levels are reached within 24 hours. Intravenous UFH typically requires hospitalization with close laboratory monitoring and dose adjustment. The most common complication is Heparin-induced thrombocytopenia.  

LMWH  

LMWH should be used whenever possible for the initial inpatient treatment of deep vein thrombosis rather than UFH. LMWH is superior to UFH for the initial treatment of deep vein thrombosis in terms of reducing mortality and the risk of major bleeding during the initial therapy.  

LMWH is now preferred over UFH in patients with acute non-massive pulmonary embolism and it is also preferred over vitamin K antagonists (VKA). LMWH or Fondaparinux is recommended over UFH for the acute-phase treatment of low- or intermediate-risk pulmonary embolism.  

It may be a treatment option for venous thromboembolism in patients with brain tumors. It is also used for the initial management of patients with phlegmasia cerulea dolens delivered in combination with aggressive leg elevation and fluid resuscitation.  

A number of studies have shown that LMWH has equal efficacy to UFH in patients with non-massive pulmonary embolism.  Patients with symptomatic pulmonary embolism should initially be treated in the hospital because of decreased cardiorespiratory reserve, complications, and for monitoring of International Normalized Ratio (INR) to guide Warfarin therapy.  

The use of LMWH is safe and effective and may shorten hospital stay and improve the quality of life for patients. Monotherapy with LMWH may be used in patients with active cancer or established renal failure and considered in patients with liver disease and coagulopathy. It may also be given concurrently with a vitamin K antagonist for patients with active cancer or antiphospholipid syndrome. Outpatient management of deep vein thrombosis should be extended to include stable patients with stable pulmonary embolism who have been carefully screened for risk factors for hemorrhage.

Laboratory monitoring is not required except for a regular platelet count before treatment initiation and on the fifth day, then every 2 to 3 days if LMWH treatment is continued.  

Fondaparinux  

Fondaparinux is also a preferred initial treatment for deep vein thrombosis and pulmonary embolism. Heparin assay (anti-factor Xa) has been used to monitor the effects of Fondaparinux. Warfarin is initiated usually within 72 hours of therapy. A platelet count should be obtained prior to the start of therapy.  

Duration of Therapy  

Treatment with UFH, LMWH, or Fondaparinux should be continued for at least 5 to 7 days after the initiation of Warfarin and until therapeutic INR is stable and ≥2.0 (range: 2.0 to 3.0) for 2 consecutive days.  

Oral Anticoagulants in the Management of Deep Vein Thrombosis and Non-massive Pulmonary Embolism  

Non-Vitamin K Antagonist Oral Anticoagulants (NOACs)

Example drugs: Apixaban, Dabigatran, Edoxaban, Rivaroxaban  

Non-vitamin K antagonist oral anticoagulants are also known as direct oral anticoagulants (DOACs). They are the recommended anticoagulant agents for patients with leg deep vein thrombosis or pulmonary embolism during the first 3 months of therapy. They are preferred over vitamin K antagonists in eligible pulmonary embolism patients for the acute-phase treatment of low- or intermediate-risk pulmonary embolism.  

Drug interactions are few, bleeding risk is low, and routine monitoring is not required. Studies suggest that non-vitamin K antagonist oral anticoagulants have a safety advantage over conventional therapy for venous thromboembolism treatment in Asian patients. They may be given to patients with renal impairment or active cancer. They may also be a treatment option for venous thromboembolism in patients with brain tumor.    

Apixaban and Rivaroxaban are given according to the single-drug approach (monotherapy) while Dabigatran and Edoxaban should be given after initial treatment with Heparin (dual therapy). For the reversal of anticoagulation, Idarucizumab may be used for patients taking Dabigatran while Andexanet alfa may be used for patients taking Apixaban or Rivaroxaban. Ciraparantag is an investigational agent that can bind and inhibit factor Xa inhibitors, UFH, LMWH, and Fondaparinux.  

Apixaban  

When Apixaban is given, prior Heparin treatment is not necessary, though short courses of Heparin should be given when there is a treatment delay. Apixaban is considered an alternative agent to LMWH for patients with cancer-associated thrombosis without high risk for gastrointestinal or genitourinary bleeding.  

Dabigatran etexilate  

Dabigatran etexilate is approved for the management of deep vein thrombosis and pulmonary embolism in patients who have been treated with parenteral anticoagulant for 5 to 10 days, and to reduce the risk of recurrent deep vein thrombosis and pulmonary embolism in patients who have been previously treated.  

Edoxaban  

Edoxaban may be used for the treatment of deep vein thrombosis and pulmonary embolism in patients who have been treated with parenteral anticoagulant for 5 to 10 days. It is considered an alternative agent to LMWH for pulmonary embolism patients with cancer (except gastrointestinal cancer).  

Rivaroxaban  

Rivaroxaban is an initial treatment for both pulmonary embolism and deep vein thrombosis without additional anticoagulation. A direct factor Xa inhibitor that is non-inferior to Warfarin in the management of acute venous thromboembolism. It is considered an alternative agent to LMWH for pulmonary embolism patients with cancer (except gastrointestinal cancer).  

Warfarin  

Warfarin is a vitamin K antagonist and is used to reduce the risk of venous thromboembolism recurrence and complications. It should only be started once venous thromboembolism has been reliably confirmed. It is started on day 1 of Heparin therapy.  

Bolus dose is not effective; therefore, it requires at least 5 days to achieve its full effects. Thus, it is recommended that Warfarin therapy overlap with parenteral anticoagulation for at least 4 to 5 days until therapeutic INR is stable and >2.0 (range: 2.0 to 3.0) in 2 consecutive readings.  

A high-loading dose (>10 mg) of Warfarin is not recommended as it has no clinical use, and it predisposes patients to hemorrhage at the start of therapy. Overdose may be reversed easily with vitamin K administration.  

Warfarin overlapping with UFH, LMWH, or dose-reduced Enoxaparin may be considered in patients with severe renal impairment, established renal failure or increased risk of bleeding. Patients with antiphospholipid antibody syndrome are recommended to undergo indefinite vitamin K antagonist treatment.  

Prompt Management of Clinical Instability  

Adrenergic Agonists  

Dobutamine  

Dobutamine is considered a first-line agent to treat right-sided heart failure and cardiogenic shock. It affects vasodilatation of both systemic and pulmonary vascular beds and increases myocardial contractility while decreasing right-sided filling pressures.  

Dopamine  

Dopamine has also been used for hemodynamic support in pulmonary embolism patients. Its use may be limited by the development of tachycardia.  

Epinephrine  

Epinephrine may be effective when shock complicates acute pulmonary embolism. Its vasoconstrictor effect is similar to Norepinephrine. Its inotropic effect is more due to potent β1 stimulation rather than the β2 effect, accounting for improved pulmonary vascular resistance.  

Norepinephrine  

Norepinephrine may be appropriate in acute massive pulmonary embolism when there is profound hypertension (eg cardiogenic shock). Norepinephrine stimulates both α-adrenergic (inducing vasoconstriction) and β1-adrenergic receptors (augmenting cardiac contractility) resulting in improved systemic blood pressure, cardiac output, pulmonary vascular resistance, and right ventricular pressure. A combination with other vasoactive agents (eg Dobutamine) needs further evaluation.  

Thrombolysis in Massive or Sub-Massive Pulmonary Embolism  

Thrombolytic Agents  

Alteplase (Recombinant Tissue Plasminogen Activator [rt-PA])  

Alteplase has comparable thrombolytic capacity to Streptokinase and Urokinase but can be administered for a shorter duration (2 hours). It is the preferred thrombolytic agent because of its shorter administration time.  

Streptokinase or Urokinase  

Streptokinase and Urokinase have similar thrombolytic effects in pulmonary embolism and have been shown to resolve pulmonary embolism comparatively at 24 hours and 3x that as seen with Heparin alone. 12 hours of Urokinase has equivalent thrombolytic efficacy to 24 hours of Streptokinase.

Nonpharmacological: Patient Education

Patient Education  

Educate patients and their families about deep vein thrombosis or pulmonary embolism, especially its signs and symptoms, risk of recurrence of disease, risk of long-term disability, and the possibility of genetic predisposition. Explain the treatment options to patients and discuss the benefits, risks, and side effects of anticoagulation therapy. Discuss lifestyle issues with patients and advise patients to drink plenty of fluids. The lay public may not be familiar with pulmonary embolism and discussing it may assuage their emotional burden.  

Bed Rest and Leg Elevation  

The affected extremity should be elevated above the level of the heart until edema and tenderness subside.  

Early Ambulation  

Early ambulation is preferred over bed rest when feasible in patients with acute deep vein thrombosis.  

Exercise  

Encourage patients confined to a chair or bed to perform regular leg exercises.  

Graduated Elastic Compression Stockings (GECS)  

Graduated elastic compression stockings provide continuous stimulation of blood flow and prevent dilation of the venous system in the legs. It counteracts increased venous pressure and improves venous flow leading to the reduction of edema and optimal calf muscle function.  

Graduated elastic compression stockings combined with early ambulation do not increase the chances of developing pulmonary embolism and provide faster resolution of pain and swelling. It is recommended to start at 1 month of diagnosis of proximal deep vein thrombosis until a minimum of 2 years to prevent post-thrombotic syndrome. Graduated compression, knee-high, custom-fitted stockings with at least 30 to 40 mmHg on the affected leg may be used. Use may be limited to 6 to 12 months in patients with proximal deep vein thrombosis and with limited signs and symptoms.  

It should be used with caution in patients with post-thrombotic syndrome. It is contraindicated in patients with peripheral artery disease or severe CHF. Some studies show the ineffectiveness of graduated elastic compression stockings for prophylaxis and they also cause lower extremity skin damage; thus, routine use of compression stockings is not recommended in patients with deep vein thrombosis, with or without an increased risk of post-thrombotic syndrome.

Invasive Procedures

In patients with cardiac arrest or refractory circulatory collapse, extracorporeal membrane oxygenation (ECMO) may be considered in combination with a catheter-directed treatment or surgical embolectomy.  

Catheter Extraction  

Catheter extraction involves the suction extraction of pulmonary embolism under fluoroscopy with ECG monitoring. This approach should be reserved for highly compromised patients who cannot receive thrombolytic therapy or whose status is so critical that it does not allow time to infuse thrombolytic therapy.  

Pulmonary Embolectomy 

Pulmonary embolectomy is performed in emergency situations when more conservative measures have failed. It should be reserved for the following patients:

• Massive pulmonary embolism (preferably angiographically documented) 
• Hemodynamic instability despite Heparin and resuscitation
• High-risk pulmonary embolism or hemodynamically deteriorating patients with failure of thrombolytic therapy or contraindication to its use

Thrombectomy  

Percutaneous Venous Thrombectomy  

Patients with acute deep vein thrombosis should not be treated with percutaneous thrombectomy alone.  

Surgical Venous Thrombectomy  

Surgical venous thrombectomy reduces acute symptoms and post-thrombotic morbidity in patients with acute iliofemoral deep vein thrombosis. These patients have extensive venous thrombosis and have contraindications for anticoagulation and thrombolytic therapy.  

Vena Caval Interruption  

Inferior Vena Caval (IVC) Filters  

Inferior vena caval filters should be considered in deep vein thrombosis or pulmonary embolism patients with contraindication or complication of anticoagulant therapy and in patients with large, free-floating iliocaval thrombus or with a pulmonary embolism that developed during anticoagulation therapy. Consider removing the inferior vena caval filter if anticoagulation has been established and is no longer contraindicated.  

Inferior vena caval may also be considered in patients who suffer from recurrent venous thromboembolism despite adequate anticoagulant therapy and patients with chronic recurrent embolism with pulmonary hypertension. It may be indicated after surgical embolectomy or pulmonary thromboendarterectomy.

It is preferable in patients with proximal deep vein thrombosis with active hemorrhage, platelet count <50,000 x 109/L, or previous intracerebral hemorrhage. It should not be used routinely in patients with deep vein thrombosis who are also being treated with anticoagulants.