eMedicine Specialties > Pulmonology > Pulmonary Embolism

Pulmonary Embolism: Treatment & Medication

Author: Nader Kamangar, MD, FACP, FCCP, FAASM,, Associate Professor of Clinical Medicine, Director of Hospitalist/Intensivist Program, Division of Pulmonary, Critical Care and Sleep Medicine, David Geffen School of Medicine at University of California Los Angeles; Associate Director, Combined Pulmonary and Critical Care Fellowship Program, Cedars-Sinai/Olive View-UCLA/West Los Angeles Veterans Affairs Medical Center
Coauthor(s): Mark S McDonnell, MD, MBA, Cardiology Fellow, University of Southern California; Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital
Contributor Information and Disclosures

Updated: Aug 25, 2009

Treatment

Medical Care

Immediate full anticoagulation is mandatory for all patients suspected to have deep vein thrombosis (DVT) or pulmonary embolism (PE). Diagnostic investigations should not delay empirical anticoagulant therapy. Current guidelines recommend starting unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux (all grade 1A) in addition to an oral anticoagulant (warfarin) at the time of diagnosis, and to discontinue UH, LMWH, or fondaparinux only after the international normalized ratio (INR) is 2.0 for at least 24 hours, but no sooner than 5 days after warfarin therapy has been started (grade 1C recommendation).33  The recommended duration of UH, LMWH, and fondaparinux is based on evidence suggesting that the relatively long half-life of factor II, along with the short half-lives of protein C and protein S, may provoke a paradoxical hypercoagulable state if these agents are discontinued prematurely.

  • Thrombolytic therapy
    • Thrombolytic therapy should be considered for patients who are hemodynamically unstable, patients who have right-sided heart strain, and high-risk patients with underlying poor cardiopulmonary reserve.
    • Although most studies demonstrate superiority of thrombolytic therapy with respect to resolution of radiographic and hemodynamic abnormalities within the first 24 hours, this advantage disappears 7 days after treatment. Controlled clinical trials have not demonstrated benefit in terms of reduced mortality rates or earlier resolution of symptoms when currently compared with heparin.
    • Until randomized clinical trials demonstrate a clear morbidity or mortality benefit, the role of thrombolytic therapy in the management of acute pulmonary embolism remains controversial. The currently accepted indications for thrombolytic therapy include hemodynamic instability or right ventricular dysfunction demonstrated on echocardiography.
  • Goals of anticoagulation therapy
    • The efficacy of heparin therapy depends on achieving a critical therapeutic level of heparin within the first 24 hours of treatment. The critical therapeutic level of heparin is 1.5 times the baseline control value or the upper limit of normal range of the activated partial thromboplastin time (aPTT).
    • This level of anticoagulation is expected to correspond to a heparin blood level of 0.2-0.4 U/mL by the protamine sulfate titration assay and 0.3-0.6 by the antifactor X assay.
    • Each laboratory should establish the minimal therapeutic level for heparin, as measured by the aPTT, to coincide with a heparin blood level of at least 0.2 U/mL for each batch of thromboplastin reagent being used.
    • If intravenous UFH is chosen, an initial bolus of 80 U/kg or 5000 U followed by an infusion of 18 U/kg/h or 1300 U/h should be given, with the goal of rapidly achieving and maintaining the aPTT at levels that correspond to therapeutic heparin levels. Fixed-dose and monitored regimens of subcutaneous UFH are available and  are acceptable alternatives.
  • Low molecular weight heparin
    • Current guidelines for patients with acute nonmassive pulmonary embolism recommend LMWH over UFH (grade 1A). In patients with massive pulmonary embolism, if concerns regarding subcutaneous absorption arise, severe renal failure exists, or if thrombolytic therapy is being considered, intravenous UFH is the recommended form of initial anticoagulation (grade 2C).33
    • LMWHs have many advantages over UFH. These agents have a greater bioavailability, can be administered by subcutaneous injections, and have a longer duration of anticoagulant effect.
    • A fixed dose of LMWH can be used, and laboratory monitoring of aPTT is not necessary.
    • Trials comparing LMWH with UFH have shown that LMWH is at least as effective and as safe as UFH.
    • The studies have not pointed to any significant differences in recurrent thromboembolic events, major bleeding, or mortality between the 2 types of heparin.
    • LMWH can be administered safely in an outpatient setting. This has lead to the development of programs in which clinically stable patients with pulmonary embolism are treated at home, at substantial cost savings.
  • Fondaparinux
    • Fondaparinux is a synthetic polysaccharide derived from the antithrombin binding region of heparin. Fondaparinux catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin.
    • Fondaparinux has not been directly compared with subcutaneous UFH or LMWH, but one randomized open-label study of 2213 patients with symptomatic pulmonary embolism compared once daily subcutaneous fondaparinux with intravenous UFH. The 2 regimens were found to have similar rates of recurrent pulmonary embolism, bleeding, and death.34
    • With the exception of patients presenting with massive pulmonary embolism (defined by hemodynamic compromise), LMWH or fondaparinux is recommended over intravenous UFH. This is because of a more predictable bioavailability, more rapid onset of full anticoagulant effect, and benefit of not typically needing to monitor anticoagulant effect.
    • However, in cases in which an anticoagulant with a shorter half-life is more desirable (ie, patients at particularly high risk of bleeding) or in patients with impaired renal function, intravenous UFH may be preferred (grade 2C).33
  • Oral anticoagulant therapy
    • The anticoagulant effect of warfarin is mediated by the inhibition of vitamin K–dependent factors, which are II, VII, IX, and X. The peak effect does not occur until 36-72 hours after drug administration, and the dosage is difficult to titrate.
    • A prothrombin time ratio is expressed as an INR and is monitored to assess the adequacy of warfarin therapy. The recommended therapeutic range for venous thromboembolism is an INR of 2-3. This level of anticoagulation markedly reduces the risk of bleeding without the loss of effectiveness. Initially, INR measurements are performed on a daily basis; once the patient is stabilized on a specific dose of warfarin, the INR determinations may be performed every 1-2 weeks or at longer intervals.
  • Duration of anticoagulation
    • A patient with a first thromboembolic event occurring in the setting of reversible risk factors such as immobilization, surgery, or trauma, should receive warfarin therapy for at least 3 months. Among patients with idiopathic (or unprovoked) first events, 2 studies have compared 6 versus 3 months of anticoagulant therapy and no difference in the rate of recurrence was observed in either study.35,36 The current recommendation is anticoagulation for at least 3 months in these patients, and the need for extending the duration of anticoagulation should be reevaluated at that time.
    • Warfarin treatment for longer than 6 months is indicated in patients with recurrent venous thromboembolism or in those in whom a continuing risk factor for venous thromboembolism exists, including malignancy, immobilization, or morbid obesity.
    • Patients who have pulmonary embolism and preexisting irreversible risk factors, such as deficiency of antithrombin III, protein S and C, factor V Leiden mutation, or the presence of antiphospholipid antibodies, should be placed on long-term anticoagulation.
  • Compression stockings: For patients who have had a proximal DVT, elastic compression stockings with a pressure of 30-40 mm Hg at the ankle for 2 years following the diagnosis is recommended (grade 1A) to reduce the risk of postphlebitic syndrome.

Surgical Care

The current grade 1A recommendation is that patients with acute pulmonary embolism should not routinely receive vena cava filters in addition to anticoagulants.33

Inferior vena cava (IVC) interruption by the insertion of an IVC filter (Greenfield filter) is only indicated in the following settings:  

  • Patients with acute venous thromboembolism who have an absolute contraindication to anticoagulant therapy (eg, recent surgery, hemorrhagic stroke, significant active or recent bleeding)
  • Patients with massive pulmonary embolism who survived but in whom recurrent embolism invariably will be fatal
  • Patients who have objectively documented recurrent venous thromboembolism, adequate anticoagulant therapy notwithstanding

An ideal IVC filter should have the following characteristics37 :  

  • Easy and safe placement by percutaneous technique
  • Biocompatible and mechanically stable
  • Ability to trap emboli without causing occlusion of the vena cava

One large trial has shown that during the first 12 days after insertion of IVC filters, significantly fewer patients had recurrent pulmonary embolism. However, following a 2-year follow-up, no significant differences in survival rates existed between the 2 groups. Furthermore, significantly higher rates of recurrent DVT occurred among patients who received an IVC filter. Other complications of IVC filters include proximal migration of the filter into the right-sided heart chambers and perforation of the IVC.38

Activity

Activity is recommended as tolerated. Early ambulation is recommended over bed rest when feasible (grade 1A recommendation).

Medication

Immediate therapeutic anticoagulation is initiated for patients with suspected deep venous thrombosis (DVT) or pulmonary embolism (PE). Anticoagulation therapy with heparin reduces mortality rates from 30% to less than 10%. Thrombolytic therapy is recommended for 3 groups of patients: (1) those patients who are hemodynamically unstable, (2) those who have right-sided heart strain, and (3) those who have limited cardiopulmonary reserve.

Chronic anticoagulation is critical to prevent relapse of DVT or pulmonary embolism following initial heparinization. The optimum duration of anticoagulation has not been well studied and is controversial. The general consensus is that a significant reduction in recurrence is associated with 3-6 months of anticoagulation.

Thrombolytics

Thrombolysis is indicated for hemodynamically unstable patients with pulmonary embolism. Thrombolysis dramatically improves acute cor pulmonale. Thrombolytic therapy has replaced surgical embolectomy as the treatment for hemodynamically unstable patients with massive pulmonary embolism.

Thrombolytic regimens currently in use for pulmonary embolism include 2 forms of recombinant tissue-plasminogen activators, alteplase (t-PA) and reteplase (r-PA), along with urokinase and streptokinase. The comparative clinical trials have shown that administration of a 1-h infusion of alteplase is more rapidly effective than urokinase or streptokinase over a 12-h period. The safety and efficacy of different thrombolytic agents is comparable. Streptokinase may cause anaphylaxis, hypotension, and other adverse reactions, leading to the cessation of therapy in many cases.

Rarely, empiric thrombolysis may be indicated in selected patients who are hemodynamically unstable, eg, the clinical likelihood of pulmonary embolism is overwhelming and the patient's condition is rapidly deteriorating (with the possibility of imminent death). In such patients, the possible risk of severe complications from thrombolysis should be carefully evaluated against the potential benefits.


Reteplase (Retavase)

Second-generation recombinant plasminogen activator that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, shown to be comparable to t-PA in achieving TIMI, 2 or 3 patency, at 90 min. Given as a single bolus or as 2 boluses administered 30 min apart.
As a fibrinolytic agent, seems to work faster than its forerunner, t-PA, and may be more effective in patients with larger clot burdens. Also reported to be more effective than other agents in lysis of older clots. Two major differences help explain these improvements. Compared with t-PA, r-PA does not bind fibrin so tightly, allowing the drug to diffuse more freely through the clot. Another advantage seems to be that it does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at the site of the clot to be transformed into clot-dissolving plasmin.
The FDA has not approved r-PA for use in patients with PE. Studies for PE have used the same dose approved by the FDA for coronary artery fibrinolysis.

Adult

10 U IV over 2 min, followed 30 min later by second dose of 10 U IV; alternatively, 20 U IV bolus as single dose

Pediatric

Not established

May increase effects of warfarin, heparin, and aspirin

Documented hypersensitivity; uncontrolled hypertension; recent intracranial surgery; malformation of aneurysm; bleeding diathesis; history of cerebrovascular accident

Pregnancy

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

Precautions

Caution with cardiovascular arrhythmias, hypotension, perfusion arrhythmias, recent major surgery, and puncture of noncompressible vessels; cerebrovascular disease; GI or GU bleeding; systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg; acute pericarditis, subacute bacterial endocarditis; hemostatic defects, including those secondary to severe hepatic or renal disease, hepatic dysfunction, pregnancy, diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site and >75 y
Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used (heparin is started when the thrombin time or the aPTT is at or below a level that is twice the normal control value); heparin should be given concurrently with r-PA for treatment of AMI; neither heparin nor aspirin should be given concurrently when used for acute ischemic stroke; coagulation studies should be performed 4 h after initiation of fibrinolytic therapy


Alteplase (Activase)

Used in management of AMI, acute ischemic stroke, and PE. Drug most often used to treat patients with PE in the ED. Usually given as a front-loaded infusion over 90-120 min. FDA-approved for this indication. Most ED personnel are familiar with its use because it is widely used for treatment of patients with AMI. An accelerated 90-min regimen is widely used, and most believe it is both safer and more effective than the approved 2-h infusion. Accelerated regimen dose is based on patient weight.
Heparin therapy should be instituted or reinstituted near the end of or immediately following infusion, when the aPTT or thrombin time returns to twice normal or less.

Adult

100 mg IV infusion over 2 h
>67 kg: 15 mg IV bolus followed by 50 mg infused over 30 min; then 35 mg infused over 60 min; not to exceed 100 mg
<67 kg: 15 mg IV bolus, followed by 0.75 mg/kg infused over 30 min; not to exceed 50 mg; then 0.5 mg/kg over 60 min; not to exceed 35 mg

Pediatric

Administer as in adults

Drugs that alter platelet function (eg, aspirin, dipyridamole, abciximab) may increase risk of bleeding prior to, during, or after t-PA therapy; may give heparin with and after t-PA infusions to reduce risk of rethrombosis; either heparin or t-PA may cause bleeding complications

Documented hypersensitivity; active internal bleeding; cerebrovascular accident or stroke within last 2 mo; intracranial or intraspinal surgery or trauma, intracranial hemorrhage on pretreatment evaluation; suspicion of subarachnoid hemorrhage; intracranial neoplasm; arteriovenous malformation or aneurysm; bleeding diathesis; severe uncontrolled hypertension

Pregnancy

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

Precautions

Monitor for bleeding, especially at arterial puncture sites, with coadministration of vitamin K antagonists; doses >0.9 mg/kg may cause ICH
Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used (heparin is started when the thrombin time or aPTT is at or below a level that is twice the normal control value); heparin should be given concurrently with r-PA for treatment of AMI; neither heparin nor aspirin should be given concurrently when used for acute ischemic stroke; coagulation studies should be performed 4 h after initiation of fibrinolytic therapy; caution in cardiovascular arrhythmias, hypotension, perfusion arrhythmias, recent major surgery, and puncture of noncompressible vessels; cerebrovascular disease; GI or GU bleeding; systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg; acute pericarditis, subacute bacterial endocarditis; hemostatic defects, including those secondary to severe hepatic or renal disease, hepatic dysfunction, pregnancy, diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site and >75 y


Urokinase (Abbokinase)

Direct plasminogen activator produced by human fetal kidney cells grown in culture. Acts on the endogenous fibrinolytic system and converts plasminogen to the enzyme plasmin, which, in turn, degrades fibrin clots, fibrinogen, and other plasma proteins. Advantage is that this agent is nonantigenic; however, more expensive than streptokinase and, thus, limits use. When used for localized fibrinolysis, given as local catheter-directed continuous infusion directly into area of thrombus with no loading dose. When used for PE, loading dose is necessary.

Adult

Loading dose: 250,000 U IV over 30 min
Maintenance dose: Infuse 100,000 U/h IV for 12-72 h

Pediatric

Loading dose: 4400 U/kg IV over 10 min
Maintenance dose: Infuse 4400 U/kg/h IV for 12-72 h

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

Documented hypersensitivity; internal bleeding; recent trauma; history of intracranial or intraspinal surgery or trauma; cerebrovascular accident; intracranial neoplasm

Pregnancy

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

Precautions

Monitor for bleeding, especially at arterial puncture sites, with coadministration of vitamin K antagonists
Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used (heparin is started when the thrombin time or aPTT is at or below a level that is twice the normal control value); neither heparin nor aspirin should be given concurrently when used for acute ischemic stroke; coagulation studies should be performed 4 h after initiation of fibrinolytic therapy; caution in cardiovascular arrhythmias, hypotension, perfusion arrhythmias, recent major surgery, and puncture of noncompressible vessels; cerebrovascular disease; GI or GU bleeding; systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg; acute pericarditis, subacute bacterial endocarditis; hemostatic defects, including those secondary to severe hepatic or renal disease, hepatic dysfunction, pregnancy, diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site and >75 y


Streptokinase (Kabikinase, Streptase)

Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots, fibrinogen, and other plasma proteins. Increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with IV infusion of streptokinase. Highly antigenic. Highly likely that treatment will be interrupted due to allergic drug reactions.
Chills, fever, nausea, and skin rashes are frequent (up to 20%). Blood pressure and heart rate drop in approximately 10% of cases during or shortly after treatment.
Late complications may include purpura, respiratory distress syndrome, serum sickness, Guillain-Barré syndrome, vasculitis, and renal or hepatic dysfunction.

Adult

Loading dose: 2000 U/kg IV over 10 min
Maintenance: 2000 U/lb/h IV for 24 h

Pediatric

Administer as in adults

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

Documented hypersensitivity; active internal bleeding; intracranial neoplasm; aneurysm; diathesis; severe uncontrolled arterial hypertension; prior exposure to drug within the past 4 y or in recent streptococcal infection

Pregnancy

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

Precautions

Monitor for bleeding, especially at arterial puncture sites, with coadministration of vitamin K antagonists
Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used (heparin is started when the thrombin time or the aPTT is at or below a level that is twice the normal control value); neither heparin nor aspirin should be given concurrently when used for acute ischemic stroke; coagulation studies should be performed 4 h after initiation of fibrinolytic therapy; caution in cardiovascular arrhythmias, hypotension, perfusion arrhythmias, recent major surgery, and puncture of noncompressible vessels; cerebrovascular disease; GI or GU bleeding; systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg; acute pericarditis, subacute bacterial endocarditis; hemostatic defects, including those secondary to severe hepatic or renal disease, hepatic dysfunction, pregnancy, diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site and >75 y

Anticoagulants

Heparin augments activity of the natural anticoagulant antithrombin III and prevents conversion of fibrinogen to fibrin. Full-dose LMWH or unfractionated IV heparin should be initiated at the first suspicion of DVT or pulmonary embolism. Heparin does not dissolve an existing clot, but it does prevent clot propagation and embolization. Recurrence or extension of DVT and pulmonary embolism may occur despite therapeutic anticoagulation with heparin.

With proper dosing, several LMWH products have been found to be safer and more effective than UFH for prophylaxis and treatment of patients with DVT and pulmonary embolism. Not necessary or useful to monitor aPTT while using LMWH. Drug is most active in tissue phase, and, as opposed to UFH, LMWH does not exert most of its effects on coagulation factor IIa.

Many different LMWH products are currently available. Because of the pharmacokinetic differences, dosing and interval of administration is highly product-specific. Presently, 3 LMWH products are available in the United States (enoxaparin, dalteparin, ardeparin). Enoxaparin is the only one that is approved by the FDA for treatment of patients with DVT. The FDA has approved all 3 for DVT prophylaxis at a lower dose. LMWH administered via subcutaneous route is preferred for commencing anticoagulation therapy. Maintenance therapy with warfarin usually is initiated simultaneously. The weight-adjusted heparin dosing regimens have proven to be efficacious for treatment of patients with DVT and pulmonary embolism and are endorsed by the experts.


Enoxaparin (Lovenox)

Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. First LMWH in United States. Only LMWH approved by FDA for treatment and prophylaxis of DVT and PE. Widely used in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as UFH.

Adult

DVT/PE: 1 mg/kg SC q12h or 1.5 mg/kg SC qd
Prophylaxis of DVT: 30 mg SC q12h
Prophylaxis in abdominal surgery: 40 mg SC qd, first dose given 2 h prior to surgery

Pediatric

DVT/PE: 1 mg/kg SC q 12h

Platelet inhibitors or oral anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine) may increase risk of bleeding

Documented hypersensitivity; major bleeding; thrombocytopenia

Pregnancy

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

Precautions

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


Dalteparin (Fragmin)

LMWH with many similarities to enoxaparin but with a different dosing schedule. Approved for DVT prophylaxis in patients undergoing abdominal surgery. Except in overdoses, no utility exists in checking PT or aPTT because aPTT does not correlate with anticoagulant effect of fractionated LMWH.

Adult

Prophylaxis in abdominal surgery: 2500 U SC qd

Pediatric

Not established

Platelet inhibitors or oral anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine) may increase risk of bleeding

Documented hypersensitivity; major bleeding; thrombocytopenia

Pregnancy

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

Precautions

If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminase levels may occur but is reversible; HAT may occur with fractionated LMWHs; 1 mg protamine sulfate reverses effect of approximately 100 U of dalteparin


Ardeparin (Normiflo)

LMWH recently released in United States for DVT prophylaxis in patients undergoing hip and knee surgery. Except in overdoses, no utility exists in checking PT or aPTT because the aPTT does not correlate with anticoagulant effect of fractionated LMWH.

Adult

DVT prophylaxis in patients undergoing hip and knee surgery: 50 U/kg SC q12h

Pediatric

Not established

Platelet inhibitors or oral anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine) may increase risk of bleeding

Documented hypersensitivity; major bleeding; thrombocytopenia

Pregnancy

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

Precautions

Reversible elevation of hepatic transaminase levels may occur; HAT has been observed with fractionated LMWH; if necessary, 1 mg protamine can neutralize 100 U of ardeparin


Heparin (Hep-Lock, Liquaemin)

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 clot after spontaneous fibrinolysis. When UFH is used, the aPTT should not be checked until 6 h after the initial heparin bolus because an extremely high or low value during this time should not provoke any action.

Adult

Initial bolus: 120-140 U/kg IV or approximately 10,000 U/70 kg; adjust dose according to desired aPTT
Initial infusion: 20 U/kg/h IV; adjust dose according to desired aPTT
If the aPTT is low (<1.5-times control value), rebolus with 5000 U and increase the drip by 10%
If aPTT is high (>2.5-times control value), decrease drip by 10%
If aPTT is extremely high (>100 s), hold drip for 1 h and decrease drip by 10%

Pediatric

Loading dose: 100 U/kg/h IV
Maintenance infusion: 15-25 U/kg/h IV
Increase dose by 2-4 U/kg/h IV q6-8h prn using aPTT results

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, ASA, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity

Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia

Pregnancy

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

Precautions

In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as a preservative; caution in severe hypotension and shock; most important risk associated with UFH is that it is ineffective because of insufficient doses; may cause hemorrhagic complications and can trigger immune thrombotic thrombocytopenia 1-2 wk after the beginning of treatment; HAT is very serious, causes widespread thrombosis that is refractory to treatment, and can be fatal if not recognized quickly and managed appropriately; if significant bleeding complications develop, 15 mg protamine (infused over 3 min) usually reverses the anticoagulant effect of UFH


Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders. Never administer to patients with thrombosis until after fully anticoagulated with heparin (first few days of warfarin therapy produce a hypercoagulable state). Failing to anticoagulate with heparin before starting warfarin causes clot extension and recurrent thromboembolism in approximately 40% of patients, compared with 8% of those who receive full-dose heparin before starting warfarin. Heparin should be continued for the first 5-7 d of oral warfarin therapy, regardless of the PT time, to allow time for depletion of procoagulant vitamin K–dependent proteins.
Tailor dose to maintain an INR in the range of 2.5-3.5. Risk of serious bleeding (including hemorrhagic stroke) is approximately constant when the INR is 2.5-4.5 but rises dramatically when the INR is >5. In the United Kingdom, higher INR target of 3-4 often is recommended.
Evidence suggests that 6 mo of anticoagulation reduces rate of recurrence to half of the recurrence rate observed when only 6 wk of anticoagulation is given. Long-term anticoagulation is indicated for patients with an irreversible underlying risk factor and recurrent DVT or recurrent PE.
Procoagulant vitamin K–dependent proteins are responsible for a transient hypercoagulable state when warfarin is first started and stopped. This is the phenomenon that occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin is always used to protect against this hypercoagulability when warfarin is started; but, when warfarin is stopped, the problem resurfaces, causing an abrupt temporary rise in the rate of recurrent venous thromboembolism.
At least 186 different foods and drugs reportedly interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep the patient adequately anticoagulated at all times because procoagulant factors recover first when warfarin therapy is inadequate.
Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K.
Foods that have moderate to high amounts of vitamin K include Brussels sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, soybean oil, soybeans, certain beans, mustard greens, peas (black-eyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.

Adult

5-15 mg/d PO qd initial; adjust dose according to desired INR

Pediatric

0.05-0.34 mg/kg/d PO; adjust dose according to desired INR

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

Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers; malignant hypertension; pregnancy

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis


Fondaparinux sodium (Arixtra)

Synthetic anticoagulant that works by inhibiting factor Xa, a key component involved in blood clotting. Provides highly predictable response. Bioavailability is 100%. Has a rapid onset of action and a half-life of 14-16 h, allowing for sustained antithrombotic activity over 24-h period. Does not affect prothrombin time or activated partial thromboplastin time, nor does it affect platelet function or aggregation.

Adult

2.5 mg SC qd

Pediatric

Not established

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

Documented hypersensitivity; seriously impaired kidney function or in patients who weigh <110 lb; patients given spinal anesthesia or spinal puncture

Pregnancy

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

Precautions

When spinal anesthesia or spinal puncture used, may develop blood clot in spine, which can result in long-term or permanent paralysis

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Multimedia: Pulmonary Embolism
References
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Further Reading

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Keywords

pulmonary embolism, pulmonary emboli, venous thromboembolism, PE, obstructive shock, deep vein thrombosis, deep venous thrombosis, DVT, hemodynamic collapse, acute pulmonary infarction, pulmonary hypertension, cor pulmonale

pleuritic chest pain, hemoptysis, venous stasis, polycythemia, immobility, hypercoagulability, factor V Leiden mutation, pancreatic carcinoma, bronchogenic carcinoma, carcinoma of the genitourinary tract, colon cancer, breast cancer, congestive heart failure, stroke, obesity, varicose veins, inflammatory bowel disease

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Contributor Information and Disclosures

Author

Nader Kamangar, MD, FACP, FCCP, FAASM,, Associate Professor of Clinical Medicine, Director of Hospitalist/Intensivist Program, Division of Pulmonary, Critical Care and Sleep Medicine, David Geffen School of Medicine at University of California Los Angeles; Associate Director, Combined Pulmonary and Critical Care Fellowship Program, Cedars-Sinai/Olive View-UCLA/West Los Angeles Veterans Affairs Medical Center
Nader Kamangar, MD, FACP, FCCP, FAASM, is a member of the following medical societies: American Academy of Sleep Medicine, American Association of Bronchology, American College of Chest Physicians, American College of Physicians, American Lung Association, American Medical Association, American Thoracic Society, California Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Mark S McDonnell, MD, MBA, Cardiology Fellow, University of Southern California
Mark S McDonnell, MD, MBA is a member of the following medical societies: American College of Physicians, American Heart Association, and American Medical Association
Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital
Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Gregory Tino, MD, Director of Pulmonary Outpatient Practices, Associate Professor, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Medical Center and Hospital
Gregory Tino, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Gregg T Anders, DO, Medical Director, Great Plains Regional Medical Command , Brook Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio
Gregg T Anders, DO is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society
Disclosure: Nothing to disclose.

 
 
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