Pulmonary Embolism (PE) Treatment & Management

Even in patients who are fully anticoagulated, however, DVT and pulmonary embolism (PE) can and often do recur. New PE in the hospital can occur in the following patients despite therapeutic anticoagulation:

• Patients who have nonfloating DVT without PE at presentation (3%)

• Patients who present with a floating thrombus but have no PE (13%)

• Patients who present with PE but have no floating thrombus (11%)

• Patients who present with PE who have a floating thrombus visible at venography (39%)

Deciding how to treat a venous thrombosis that may lead to a PE is difficult. A survey of Canadian pediatric intensivists reported the following four patient factors commonly used to determine if a venous thrombosis is clinically important ^[26] :

• Clinical suspicion of a PE

• Symptoms

• Detection of thrombosis on clinical examination

• Presence of an acute or chronic cardiopulmonary comorbidity that affects the patient's ability to tolerate a PE

Anticoagulants are the treatment of choice in most children with pulmonary emboli. Thrombolytics are rarely used. To date, little data are available regarding the use of LMWH in children with thromboembolic disease.

All patients with PE require rapid risk stratification. Thrombolytic therapy should be used in patients with acute PE associated with hypotension (systolic BP< 90 mm HG) who do not have a high bleeding risk. ^[5] Do not delay thrombolysis in this population because irreversible cardiogenic shock can develop. Thrombolytic therapy is suggested in select patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation or clinical course after starting anticoagulation suggests a high risk of developing hypotension. Assessment of pulmonary embolism severity, prognosis, and risk of bleeding dictate whether thrombolytic therapy should be started. Thrombolytic therapy is not recommended for most patients with acute PE not associated with hypotension. ^[5]

Although most studies demonstrate the superiority of thrombolytic therapy with respect to the resolution of radiographic and hemodynamic abnormalities within the first 24 hours, this advantage disappears 7 days after treatment. Controlled clinical trials have not demonstrated benefits in terms of reduced mortality rates or earlier resolution of symptoms when currently compared with heparin. A large retrospective review suggests that the use of thrombolytic therapy in unstable patients with PE may lead to reduced mortality when compared to anticoagulation therapy alone. Concurrent use of thrombolytic therapy and vena cava filters in such patients may reduce mortality even further. ^{[81, 82]}

In a meta-analysis of 16 randomized studies comparing thrombolytic therapy with anticoagulation therapy in patients with pulmonary embolism, including intermediate-risk, hemodynamically stable patients with right ventricular dysfunction, Chatterjee et al found that thrombolytic therapy, as compared with standard anticoagulant therapy, reduced mortality by 47% but was associated with a 2.7-fold increase in major bleeding. ^[83]

The investigators also found, however, that the rate of major bleeding was not significantly increased with thrombolysis among patients younger than 65 years, whereas it more than tripled in the subgroup of patients older than 65 years. ^[83] Thrombolytic therapy was associated with a greater risk of intracranial hemorrhage and a lower risk of recurrent pulmonary embolism. ^[83]

Until randomized clinical trials demonstrate a clear morbidity or mortality benefit, the role of thrombolytic therapy in the management of acute pulmonary embolism will remain controversial (especially in the management of intermediate-risk patients). ^{[84, 85, 86]} The currently accepted indications for thrombolytic therapy include hemodynamic instability (systolic BP < 90 mm Hg) or a clinical risk factor assessment that suggests that hypotension is likely to develop.

Unfractionated heparin therapy

In patients with acute PE, anticoagulation with IV UFH, LMWH, or fondaparinux is preferred over no anticoagulation. ^[5] Most patients with acute PE should receive LMWH or fondaparinux instead of IV UFH. In patients with PE, if concerns regarding subcutaneous absorption arise, severe renal failure exists, or if thrombolytic therapy is being considered, IV UFH is the recommended form of initial anticoagulation. ^[5] Clinicians often choose to use IV UFH in preference to LMWH and fondaparinux in specific clinical circumstances where medical or surgical procedures are likely to be performed and the short half-life of IV UFH allows for temporary cessation of anticoagulation and presumed reduction of bleeding risk during the procedure. Though this strategy has limited supporting evidence, it appears to represent a reasonable practice.

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 anti-factor 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 IV 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 therapy

Current guidelines for patients with acute PE recommend LMWH over IV UFH (grade 2C) and over SC UFH (grade 2B). ^[5] In patients being treated with LMWH, once-daily regimens are preferred over twice-daily regimens (grade 2C). The choice between fondaparinux and LMWH should be based on local considerations to include cost, availability, and familiarity of use.

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 led to the development of programs in which clinically stable patients with PE are treated at home, at substantial cost savings. The ACCP guidelines suggest that patients with low-risk PE and who have acceptable home circumstances be discharged early from hospital (ie, before the first five days of treatment)(grade 2B).

An international, open-label, randomized trial compared outpatient and inpatient treatment (both using the LMWH enoxaparin as initial therapy) of low-risk patients with acute PE and concluded that outpatient treatment was noninferior to inpatient treatment. ^[87]

Direct thrombin inhibitors and factor Xa inhibitors

Apixaban, dabigatran, rivaroxaban, and edoxaban are alternatives to warfarin for prophylaxis and treatment of PE. Apixaban, edoxaban, and rivaroxaban inhibit factor Xa, whereas dabigatran is a direct thrombin inhibitor.

Rivaroxaban

Rivaroxaban (Xarelto) is an oral factor Xa inhibitor approved by the FDA in November 2012 for the treatment of DVT or PE, and to reduce risk of recurrent DVT and PE following initial treatment.

Approval for this indication was based on studies totaling 9478 patients with DVT or PE. Participants were randomly assigned to receive rivaroxaban, a combination of enoxaparin and a vitamin K antagonist (VKA) (eg, warfarin), or a placebo. Study endpoints were designed to measure the number of patients who experienced recurrent symptoms of DVT, PE, or death after receiving treatment. ^{[88, 89]} Additionally, results from extended treatment demonstrated a reduced risk of recurrent DVT and PE. Approximately 1.3% in the rivaroxaban group experienced recurrent DVT or PE compared with 7.1% in the placebo group. ^{[90, 91]}

The results of the Einstein-PE study provide an important advance in the treatment of symptomatic PE. In a prospective, open-label study, 4832 patients were randomized to receive either rivaroxaban or enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. Treatment with a fixed-dose regimen of rivaroxaban was noninferior to standard therapy and had a satisfactory safety profile. ^[88]

Data from a pooled analysis of the EINSTEIN-PE and EINSTEIN-DVT studies in the treatment of DVT or pulmonary embolism suggest that rivaroxaban is as effective in preventing VTE recurrence as administration of enoxaparin followed by a vitamin-K antagonist. ^{[92, 93]} Rivaroxaban may also be associated with less bleeding, particularly in elderly patients and those with moderate renal impairment. ^{[92, 93]}

Rivaroxaban use for VTE prevention in acutely ill medical patients with restricted mobility demonstrated noninferiority to enoxaparin in short-term use (10 ± 4 days) and superiority in long-term use (35 ± 4 days) compared with short-term use of enoxaparin followed by placebo. ^[94]   Another study failed to show a significant benefit of rivaroxaban over placebo in reducing the composite end point of symptomatic VTE or death in medically ill patients at increased risk for VTE after discharge; however, there were few events and the primary safety outcome, major bleeding, was not significantly increased with treatment. ^[95]

Apixaban

Apixaban was approved for treatment of PE in August 2014. The approval for treatment of PE and prevention of recurrence was based on the outcome of the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) and AMPLIFY-EXT studies, in which apixaban therapy was compared with enoxaparin and warfarin treatment. The AMPLIFY study showed that, in comparison with the standard anticoagulant regimen apixaban therapy resulted in a 16% reduction in the risk of a composite endpoint that included recurrent symptomatic venous thromboembolism (VTE) or VTE-associated death. ^{[96, 97]}

This advance thus offers the prospect of a safe and effective regimen of anticoagulation for patients with the advantages of simplicity and cost-effectiveness in comparison to current management strategies.

Dabigatran

Dabigatran (Pradaxa) was approved by the FDA in 2014 for the treatment of DVT and PE and reducing venous thromboembolic recurrence. In the RE-COVER and RE-COVER 2 studies, patients with DVT and PE who had received initial parenteral anticoagulation (eg, IV heparin, SC LMWH) for 5-10 days were randomized to warfarin or dabigatran. These two trials showed dabigatran was noninferior to warfarin in reducing DVT and PE and was associated with lower bleeding rates. ^{[98, 99]}

Edoxaban

Edoxaban (Savaysa) was approved by the FDA in January 2015 for the treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days. Approval was based on the Hokusai-VTE study, which included 3,319 patients with PE. Of these patients, 938 had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels. The rate of recurrent VTE in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group. Edoxaban was noninferior to high-quality standard warfarin therapy and caused significantly less bleeding in a broad spectrum of patients with VTE, including those with severe pulmonary embolism. ^[100]

Betrixaban

Betrixaban, a factor Xa inhibitor, was approved by the FDA in June 2017. It is indicated for prophylaxis of VTE in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE.

Approval of betrixaban was based on data from the phase 3 APEX studies. These randomized, double-blind, multinational clinical trials compared extended-duration betrixaban (35-42 days) to short-duration enoxaparin (6-14 days) for VTE in 7513 acutely medically ill hospitalized patients with VTE risk factors.

Patients in the betrixaban group took an initial dose of 160 mg orally on day 1, followed by 80 mg once daily for 35-42 days, and received a placebo injection once daily for 6-14 days. Patients in the enoxaparin group received 40 mg subcutaneously once daily for 6-4 days and took an oral placebo once daily for 35-42 days.

Efficacy was measured in 7441 patients using a composite outcome score composed of the occurrence of asymptomatic or symptomatic proximal deep vein thrombosis, nonfatal pulmonary embolism, stroke, or VTE-related death. Betrixaban showed significant decreases in VTE events compared with enoxaparin. ^{[101, 102]}

Fondaparinux

In patients with acute PE, fondaparinux as initial treatment is favored over IV UFH and over SC UFH. ^[5] The choice between fondaparinux and LMWH should be based on local considerations to include cost, availability, and familiarity of use. Fondaparinux is a synthetic polysaccharide derived from the antithrombin binding region of heparin. Fondaparinux catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin.

Once-daily fondaparinux was found to have similar rates of recurrent PE, bleeding, and death as IV UFH, according to one randomized open-label study of 2213 patients with symptomatic pulmonary embolism. ^[103]

In general, the use of LMWH or fondaparinux is recommended over IV UFH and SC UFH. This is because of a more predictable bioavailability, more rapid onset of full anticoagulant effect, and the benefit of not typically needing to monitor anticoagulant effect. However, if uncertainty arises regarding the accuracy of dosing, factor Xa levels can be monitored to determine efficacy.

Warfarin therapy

A vitamin K antagonist such as warfarin should be started on the same day as anticoagulant therapy in patients with acute PE. ^[5] Parenteral anticoagulation and warfarin should be continued together for a minimum of at least five days and until the INR is 2.0.

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 therapy

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. No difference in the rate of recurrence was observed in either of 2 studies comparing 3 versus 6 months of anticoagulant therapy in patients with idiopathic (or unprovoked) first events. ^{[104, 105]} The current recommendation is anticoagulation for at least 3 months in these patients; the need for extending the duration of anticoagulation should be reevaluated at that time.

The current ACCP guidelines recommend that all patients with unprovoked PE receive three months of treatment with anticoagulation over a shorter duration of treatment and have an assessment of the risk-benefit ratio of extended therapy at the end of three months (grade 1B). ^[5] Patients with a first episode of venous thromboembolism and with a low or moderate risk of bleeding should have extended anticoagulant therapy (grade 2B). Patients with a first episode of venous thromboembolism who have a high bleeding risk should have therapy limited to three months (grade 1B).

In patients with a second unprovoked episode of venous thromboembolism and low or moderate risk of bleeding, extended anticoagulant therapy is recommended (grades 1B and 2B, respectively). In patients with a second episode of venous thromboembolism and a high risk of bleeding, three months of anticoagulation is preferred over extended anticoagulation (grade 2B).

Patients who have PE 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.

Cancer patients

Patients who have PE in association with an active neoplasm provide challenges for long-term management because of their increased continuing risk for recurrent VTE and PE. The ninth edition of the ACCP guidelines recommends that such patients receive extended anticoagulation as opposed to three month therapy if they are at low or moderate risk of bleeding complications (grade 1B). ^[5] If patients with active neoplasm are at high risk of bleeding, it is still suggested that they receive extended therapy, though the supporting evidence is less conclusive (grade 2B). For the treatment of PE in cancer patients, LMWH is recommended in preference to a vitamin K antagonist such as warfarin (grade 2B). However, some cancer patients choose not to have long-term treatment with LMWH because of the need for daily injections and treatment costs. If cancer patients with PE choose not to have treatment with LMWH, a vitamin K antagonist such as warfarin is preferred over dabigatran or rivaroxaban (grade 2C).

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin. The main features of HIT are (1) thrombocytopenia resulting from immunoglobulin G–mediated platelet activation and (2) in vivo thrombin generation and increased risk of venous and arterial thrombosis.

The highest frequency of HIT, 5%, has been reported in post–orthopedic surgery patients receiving up to 2 weeks of unfractionated heparin. HIT occurred in approximately 0.5% of post–orthopedic surgery patients receiving LMWH for up to 2 weeks.

HIT may manifest clinically as extension of the thrombus or formation of new arterial thrombosis. HIT should be suspected whenever the patient's platelet count falls to less than 100,000/µL or less than 50% of the baseline value, generally after 5-15 days of heparin therapy. For patients receiving heparin where the risk of HIT is thought to be greater than 1%, guidelines suggest that platelet counts be obtained every two or three days from day 4 to day 14 of therapy, or until the heparin is stopped (grade 2C). ^[5] The definitive diagnosis is made by performing a platelet activation factor assay.

The treatment of patients who develop HIT is to stop all heparin products, including catheter flushes and heparin-coated catheters, and to initiate an alternative, nonheparin anticoagulant, even when thrombosis is not clinically apparent. In patients with HIT with or without thrombosis, the use of lepirudin, argatroban, or danaparoid is preferred over continued use of heparin, LMWH, or either initiation or continuation of a vitamin K antagonist (grade 1C). ^[5]

If a vitamin K antagonist has already been started when HIT is diagnosed, guidelines recommend that it be discontinued and that vitamin K should be administered (grade 2C). ^[5] When HIT has been confirmed, vitamin K antagonists should not be started until the platelet count has recovered to at least 150 x 10⁹/L (grade 1C), it should be started at low doses (ie, 5 mg of warfarin), and it should be given concomitantly with a nonheparin anticoagulant for a minimum of five days and until the INR is within the target range (grade 1C). ^[5] In patients with renal failure who have HIT and thrombosis, argatroban is preferred over other nonheparin anticoagulants (grade 2C). ^[5]

Resistance to heparin

Few patients with venous thromboembolism require large doses of heparin for achieving an optimal activated partial thromboplastin time (aPTT). Those patients who do require them have increased plasma concentrations of factor VIII and heparin-binding proteins. Increased factor VIII concentration causes dissociation between aPTT and plasma heparin values. The aPTT is suboptimal, but patients have adequate heparin levels upon protamine titration. This commonly occurs in patients with a concomitant inflammatory disease.

Monitoring the antifactor Xa assay results in this situation is safe and effective and results in less escalation of the heparin dose when compared with monitoring with aPTT. Whenever a therapeutic level of aPTT cannot be achieved with large doses of UFH, either determination of plasma heparin concentration or therapy with LMWH should be instituted.

Either catheter embolectomy and fragmentation or surgical embolectomy is reasonable for patients with massive pulmonary embolism who have contraindications to fibrinolysis or who remain unstable after receiving fibrinolysis. ^[106] If these procedures are not available locally, it is reasonable to consider transferring the patient to an institution with experience in one of these procedures, providing the transfer can be accomplished safely.

In patients with submassive acute PE, either catheter embolectomy or surgical embolectomy may be considered if they have clinical evidence of an adverse prognosis (ie, new hemodynamic instability, worsening respiratory failure, severe right ventricular dysfunction, or major myocardial necrosis). These interventions are not recommended for patients with low-risk or submassive acute pulmonary embolism who have minor right ventricular dysfunction, minor myocardial necrosis, and no clinical worsening. ^[106]

Patients with acute PE should not routinely receive vena cava filters in addition to anticoagulants. ^[5] An ideal IVC filter should be easily and safely placed using a percutaneous technique, biocompatible and mechanically stable, and able to trap emboli without causing occlusion of the vena cava. ^[107]

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 PE who survived but in whom recurrent embolism invariably will be fatal

• Patients who have objectively documented recurrent venous thromboembolism, adequate anticoagulant therapy notwithstanding

In patients with a time-limited indication for IVC filter placement (eg, a short-term contraindication to anticoagulation), it is reasonable to select a retrievable IVC filter and evaluate the patient periodically for filter retrieval. After placement of an IVC filter, anticoagulation should be resumed once contraindications to anticoagulation or active bleeding complications have resolved. ^[106]

Compression stockings

For patients who have had a proximal DVT, the use of elastic compression stockings provides a safe and effective adjunctive treatment that can limit postphlebitic syndrome. Stockings with a pressure of 30-40 mm Hg at the ankle, worn for 2 years following diagnosis, are recommended (grade 2B) to reduce the risk of postphlebitic syndrome.

True gradient compression stockings are highly elastic, providing a gradient of compression that is highest at the toes and gradually decreases to the level of the thigh. This reduces capacitive venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of 5 or more. Compression stockings of this type have been proven effective in the prophylaxis of thromboembolism and are also effective in preventing progression of a blood clot in patients who already have DVT and pulmonary embolism.

A 1994 meta-analysis calculated a DVT risk odds ratio of 0.28 for gradient compression stockings (as compared to no prophylaxis) in patients undergoing abdominal surgery, gynecologic surgery, or neurosurgery.

Other studies found that gradient compression stockings and LMWH were the most effective modalities in reducing the incidence of DVT after hip surgery; they were more effective than subcutaneous UFH, oral warfarin, dextran, or aspirin.

The ubiquitous white stockings known as anti-embolic stockings or "Ted hose" produce a maximum compression of 18 mm Hg. Ted hose rarely are fitted in such a way as to provide even that inadequate gradient compression. Because they provide such limited compression, they have no efficacy in the treatment of DVT and pulmonary embolism, nor have they been proven effective as prophylaxis against a recurrence.

True 30-40 mm Hg gradient compression pantyhose are available in sizes for pregnant women. They are recommended by many specialists for all pregnant women because they not only prevent DVT, but they also reduce or prevent the development of varicose veins during pregnancy.

Additional support therapies

Activity is recommended as tolerated. Early ambulation is recommended over bed rest when feasible (grade 2C recommendation).

Pharmacologic support of the cardiovascular system may be necessary. Dopamine and dobutamine are the usual inotropic agents. Mechanical ventilation may be necessary to provide respiratory support and as adjunctive therapy for a failing circulatory system.

Children with sickle cell disease who present with pulmonary symptoms require treatment with a macrolide and cephalosporin antibiotic. Their clinical status should be closely monitored in order to anticipate those children who may develop acute chest syndrome. ^[45] Transfusion with packed red blood cells (either simple or exchange) improves oxygenation immediately, helping to break the vicious cycle outlined above.

IV fluids may help or may hurt the patient who is hypotensive from pulmonary embolism, depending on which point on the Starling curve describes the patient's condition. A cautious trial of a small fluid bolus may be attempted, with careful surveillance of the systolic and diastolic blood pressures and immediate cessation if the situation worsens after the fluid bolus. Improvement or normalization of blood pressure after fluid loading does not mean the patient has become hemodynamically stable.

Individuals with acute, submassive pulmonary embolisms have low levels of endogenous activated protein C. A study by Dempfle et al determined that administering drotrecogin alfa (activated) along with therapeutic doses of enoxaparin enhanced the inhibition of fibrin formation in these patients. ^[108]

Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011 after analysis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial. Drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.

PT should be measured on a regular basis; the goal is an INR of 2-3.

The length of treatment depends on the presence of risk factors. If no underlying risk factors are present, therapy can be stopped within 1-2 months. If risk factors are present, especially anticardiolipin antibodies, therapy should continue for at least 4-6 months.

Long-term anticoagulation is essential for patients who survive an initial DVT or pulmonary embolism. The optimum total duration of anticoagulation is controversial, but general consensus holds that at least 6 months of anticoagulation is associated with significant reduction in recurrences and a net positive benefit. ^[109]

Patients may have treatment initiated using concomitant warfarin and unfractionated heparin for 5 days in the hospital, with discharge on warfarin alone when the international normalized ratio (INR) is 2. Alternatively, patients may be discharged on concomitant therapy with a LMWH and warfarin for at least 5 days. The LMWH is then discontinued in the outpatient setting when the INR reaches 2.

The risk of venous thromboembolism is increased during pregnancy and the postpartum period. Pulmonary embolism is the leading cause of death in pregnancy. DVT and pulmonary embolism are common during all trimesters of pregnancy and for 6-12 weeks after delivery.

Diagnosis

The diagnostic approach to patients with pulmonary embolism should be exactly the same in a pregnant patient as in a nonpregnant one. A nuclear perfusion lung scan is safe in pregnancy, as is a chest CT scan.

Guidelines by the professional societies on the diagnosis of pulmonary embolism make this difficult assessment easier and reduce the risks of radiation to the fetus. If the patient has a low pretest probability for pulmonary embolism and a normal D-dimer test result, clinical exclusion from further investigations is recommended. When the suspicion is high, the patients should have bilateral leg Doppler assessment. If the results are positive, the patient should be treated for pulmonary embolism. If the results are negative, CT pulmonary angiography is the next step. To rule out contrast-induced hypothyroidism, all neonates exposed to the iodinated contrast in utero should have their serum thyrotropin level checked in the first week of life.

Treatment

Heparin and fibrinolysis are safe in pregnancy. Failure to treat the mother properly is the most common cause of fetal demise.

Pregnant patients diagnosed with DVT or pulmonary embolism may be treated with LMWH throughout their pregnancy. Warfarin is contraindicated, because it crosses the placental barrier and can cause fetal malformations. Unfractionated heparin is category C. Therefore, LMWH at full anticoagulation doses should be continued until delivery. Women experiencing a thromboembolic event during pregnancy should receive therapeutic treatment with unfractionated heparin or LMWH during pregnancy, with anticoagulation continuing for 4-6 weeks postpartum and for a total of at least 6 months.

In addition to the thrombotic risks in pregnancy, women of childbearing age who are prescribed warfarin should be advised of the teratogenic effects of this drug. Alteplase is a category C drug, and should only be given following a judicious assessment of the risk-to-benefit ratio.

Pregnant women who are in a hypercoagulable state or who have had previous venous thromboembolism should receive prophylactic anticoagulation during pregnancy.

Fibrinolytic therapy should not be delayed while consultation is sought. The decision to treat pulmonary embolism by fibrinolysis is properly made by the responsible emergency physician alone, and fibrinolytic therapy is properly administered in the ED.

A pulmonologist is often consulted before the true diagnosis is made because of the nonspecific nature of the symptoms, and consultation with a cardiologist is warranted to rule out a cardiac etiology for the presenting symptoms and signs and to perform ECHO and pulmonary angiography.

If embolectomy is considered, consultation with a cardiac surgeon is mandatory. Few data are available regarding the use of surgical embolectomy in children. Consider embolectomy in the setting of massive cardiac failure when time is insufficient for natural or pharmacologic thrombolysis or if thrombolysis is contraindicated. Thrombotic endarterectomy is another surgical treatment option for patients with hemodynamic compromise from large pulmonary emboli. Thrombotic endarterectomy is only performed at certain centers and has a high mortality rate, but it can be successful in certain populations.

A hematologist can suggest an appropriate workup for a procoagulant defect and can recommend an anticoagulation regimen. Consultation with a hematologist is essential in children with sickle cell disease. A free clinical consultation service for complex cases of thromboembolism in children is available for clinicians by calling 1-800-NO-CLOTS (1-800-662-5687).

An interventional radiology consultation may be helpful for catheter-directed fibrinolysis in selected patients. In rare cases, arranging for placement of a venous filter may be appropriate if the patient is not a candidate for thrombolytic therapy.

Preventing idiopathic outpatient pulmonary embolism is difficult, if not impossible. That said, the majority of pulmonary embolisms occur in hospitalized patients. The incidence in these cases can be reduced through appropriate prophylaxis, achieved mechanically or via the administration of heparin, LMWH, or warfarin. ^[5]

The incidence of venous thrombosis, pulmonary embolism, and death can be significantly reduced by embracing a prophylactic strategy in high-risk patients. Prevention of DVT in the lower extremities inevitably reduces the frequency of pulmonary embolism; therefore, populations at risk must be identified, and safe and efficacious prophylactic modalities should be used.

Regular physical exercise, leg elevation, and wearing compression stockings may aid in preventing pulmonary embolism.

The QThrombosis algorithm is intended to identify currently asymptomatic adults at greatest future risk of venous thrombosis based on established risk factors. According to the study in which it was developed and validated, QThrombosis estimates the absolute risk of venous thrombosis at 1 year and 5 years into the future, information that can be used to guide prophylaxis and medication decisions. ^[110]

Pulmonary embolism is an extremely common disorder. It presents with nonspecific clinical features and requires specialized investigations for confirmation of diagnosis. Therefore, many patients die from unrecognized pulmonary embolism. The other common pitfalls are as follows:

• Disregarding patient's complaints of unexplained dyspnea as anxiety or hyperventilation

• Blaming complaints of unexplained chest pain on musculoskeletal pain

• Failing to recognize, diagnose, and treat DVT

• Failing to initiate an appropriate diagnostic workup in patients with symptoms consistent with pulmonary embolism

• Failing to initiate therapeutic anticoagulant therapy with heparin in patients suspected to have pulmonary embolism, before the V/Q scan or other investigations

• Failure to advise of risk factors, such as smoking, pregnancy, and use of the oral contraceptive pill

• Failure to diagnose predisposing or associated conditions

Advances over the past several decades have significantly improved physicians’ ability to diagnosis pulmonary embolism and have refined the treatment of this disorder. However, several areas need further research and properly conducted therapeutic trials. The role of LMWH and the optimal duration of anticoagulant therapy in different subgroups of patients with venous thromboembolism require further study.

Because warfarin therapy results in bleeding, future studies should determine whether less intense warfarin therapy is effective in preventing recurrences of pulmonary embolism.

Whether drugs that inhibit the action of thrombin (eg, hirudin) are useful in treating patients with venous thromboembolic disease also needs to be determined by future trials.