Paradoxical Embolism 

Updated: Aug 11, 2020
Author: Igor A Laskowski, MD; Chief Editor: Vincent Lopez Rowe, MD 


Practice Essentials

The clinical manifestations of paradoxical embolism (PDE) are nonspecific, and the diagnosis is difficult to establish.[1, 2]  Patients with PDE may present with neurologic abnormalities or features suggesting arterial embolism. The disease starts with the formation of emboli within the venous system, which traverse a patent foramen ovale (PFO) and enter the systemic circulation.[3, 4, 5]  PFOs have been found on autopsy in up to 35% of the healthy population.

PDE originates in the veins of the lower extremities and occasionally in the pelvic veins. Emboli may be of various types, such as clots, air, tumor, fat, and amniotic fluid.[6]  Septic emboli have led to brain abscesses. Projectile embolization (eg, from a shotgun pellet) is rare.

PDE is considered the major cause of cerebral ischemic events in young patients. On rare occasions, it may occlude the pelvic aortic bifurcation. The largest documented thrombus in a PFO (impending PDE) was 25 cm long.

PDE is confirmed by the presence of thrombus within an intracardiac defect on contrast echocardiography or at autopsy. It may be presumed in the presence of arterial embolism with no evidence of left-side circulation thrombus, deep venous thrombosis (DVT) with or without pulmonary embolism (PE), and right-to-left shunting through an intracardiac communication, commonly the PFO.[7]

Treatment of PDE involves medical intervention, surgical intervention, or both. The initial treatment is anticoagulation to prevent propagation of an intracardiac clot. Drugs used to treat PDE include anticoagulants, antiplatelet agents, and thrombolytics. Embolectomy and closure of an intracardiac communication (eg, a PFO or an atrial septal defect [ASD]) are the surgical treatments of choice and are widely used in patients with presumed PDE.

The presence of PDE in association with PE or atrial clots increases mortality. No difference in survival exists between patients treated medically and those treated surgically.


PDE originates from a venous thrombosis (see the image below). In most cases, the source is in the deep veins of the lower extremities; thrombosis occurs less frequently in the upper extremities than in the lower extremities. The thrombus is composed of platelets, fibrin, and, eventually, red blood cells (RBCs). It tends to propagate in the direction of the blood flow.

Paradoxical embolism. Paradoxical embolism.

Many conditions predispose individuals to increased risk for development of venous thrombosis, including the following:

Risk factors include the following:

  • Immobilization
  • Pregnancy
  • Estrogen use
  • Previous DVT
  • Trauma
  • Neoplasms (ie, breast, pelvic malignancy, stomach, pancreas, lung)
  • Surgery (especially orthopedic, abdominal, and genitourinary procedures)
  • Thromboangiitis obliterans (Buerger disease) and homocystinuria – These two types of venulitis are among the least common risk factors

The intracardiac communication between the venous and arterial circulations can be in the form of a PFO, an ASD, a pulmonary arteriovenous malformation (AVM), a ventricular septal defect (VSD), an Ebstein anomaly, or a patent ductus arteriosus.

A PFO is defined as a valvelike opening between the septum primum and the septum secundum without evidence of an anatomic septal defect. PFO is significant in the etiology of PDE if associated right-to-left shunting is present. Causes of right-to-left shunting include the following:

  • Right atrial hypertension
  • Right ventricular hypertension
  • Right ventricular failure with increased end-diastolic pressure; positive-pressure ventilation
  • Positive end-expiratory pressure
  • Pulmonary hypertension from hypoxemia
  • Myocardial infarction (MI) of the right side of the heart
  • Valsalva-type maneuvers (forced expiration against a closed glottis), including urination, defecation, and sneezing

The clinical manifestations are based on complications of embolism and depend on the site of the embolus; multiorgan ischemia and infarction can occur. PE is a prerequisite for PDE. If the left pulmonary artery is occluded suddenly, the mean pulmonary artery pressure increases by 30% from the baseline. According to estimates, PE may lead to PDE only if it produces a rise in mean pulmonary artery pressure greater than 30 mm Hg, facilitating an increase in right atrial pressure above left atrial pressure that results in right-to-left shunting.

The PFO increases in size with advancing age, from a mean of 3 mm in the first decade to 6 mm in the 10th decade.


Many conditions predispose individuals to increased risk for DVT, including the following:

  • Hypercoagulable states, such as factor V Leiden (resistance to activated protein C); antithrombin III, protein C, and protein S deficiencies; antiphospholipid antibody syndrome; prothrombin mutation; and dysfibrinogenemia
  • Previous DVT
  • Immobilization
  • Pregnancy and estrogen use
  • Neoplasms (eg, of the breast, pelvis, or stomach)
  • Abdominal and thoracic surgical procedures
  • Orthopedic and genitourinary surgical procedures
  • Trauma
  • Venulitis (eg, thromboangiitis obliterans [Buerger disease] and homocystinuria)

Intracardiac communication of the venous and arterial circulations can lead to PDE and may occur via the following:

  • PFO
  • ASD
  • Pulmonary AVM
  • VSD
  • Ebstein anomaly
  • Patent ductus arteriosus

It has been suggested that cardiopulmonary resuscitation (CPR) could cause PDE by producing a sudden increase in right atrial pressure during the compression phase and thereby giving rise to a right-to-left shunt.[8]


United States statistics

The actual frequency of PDE has not been definitively established, because most cases are presumed rather than proved and most cryptogenic strokes are not investigated.

PDE may be common. The incidence of stroke in the United States is approximately 500,000 per year. Of all strokes, 35-40% are cryptogenic (ie, without an identifiable source). PFOs are found in approximately 20-30% of those who sustain cryptogenic strokes. Autopsy data suggest that PFO may be present in 25-35% of the normal population. Right-to-left atrial shunts in PDE are associated with an underlying PFO in approximately 70% of case series and autopsy reports.

DVT may escape clinical detection in more than 50% of cases. Venous thrombosis may occur in more than 50% of orthopedic surgical procedures and in more than 20% of patients who undergo abdominal or thoracic surgical procedures.

The clinical findings of PDE are arterial embolic manifestations that include cerebral (40%), peripheral (50%), coronary (8%), renal (1%), and splenic (1%) ischemia or infarction. PE has been demonstrated in as many as 85% of diagnosed cases of PDE. Chronically elevated pressures of the right side of the heart are associated with 5% of PDE cases.

Age-, sex-, and race-related demographics

Elderly patients are commonly affected; PDE is not common in children. The risk of DVT is increased in the elderly population; this is correlated with the increased incidence of PDE in patients older than 55 years. Elderly patients may be at increased risk for the passage of thrombus through a PFO. The size of the PFO is usually greater in this age group than in younger populations; the average size of a PFO is 3 mm in the first decade of life versus 6 mm in the 10th decade of life.

PDEs do occur in individuals younger than 55 years when an intracardiac communication is present with risk of DVT and right-to-left atrial shunting. PFO with atrial right-to-left shunting is the most frequent cardiac finding in patients younger than 55 years with an otherwise unexplained ischemic cerebral insult or cryptogenic stroke.

The sexes are equally represented in the demographics of the disease because there is no sex-related difference in the incidence of PFO in the normal population. No established differences exist across racial or ethnic groups.


PDE generally has a good prognosis when it is not complicated. Morbidity and mortality are increased in patients with PDE and PE, depending on the size of the embolus and end-organ lodgment. When impending PDE occurs, the choice of treatment involves open-heart surgery.

Some patients with PDE experience devastating outcomes with complications such as neurologic deficits, blindness, gangrene of extremities, and amputation, depending on whether the limb is salvageable or not. Organ damage may include renal infarction with eventual renal insufficiency.

Patient Education

Patients on long-term anticoagulant therapy should be educated in the importance of compliance with their medication regimen for prevention of recurrent thromboembolic events. They should also be instructed to avoid vitamin K–containing foods such as green leafy vegetables (eg, spinach, broccoli, and cauliflower).

Varicose veins coexist commonly with cyanotic congenital heart disease, and these may predispose to thromboembolic phenomena. Accordingly, patients with varicose veins should avoid passive standing, should avoid crossing their legs when sitting, and should not allow their legs to be dependent.

To prevent elevation of the right atrial pressure above the left atrial pressure, which can lead to transient right-to-left shunting in patients with risk factors for PDE, Valsalva maneuvers should be avoided.

Patients should be educated regarding the adverse reactions from intravenous contrast agents that may occur in studies such as venography, arteriography, angiography, and cardiac catheterization (see Workup). Obtaining an informed consent after providing full explanation of the indications, implications, and complications of the procedure and the possibility of contrast-associated adverse reactions is important.

For patient education resources, see the Circulatory Problems Center, as well as Blood Clot in the Legs.




The clinical findings of paradoxical embolism (PDE) are nonspecific and are related to other disease entities such as pulmonary embolism (PE), neurologic deficits associated with transient ischemic attack (TIA) or embolic stroke, and systemic arterial embolism. The clinical triad of PDE consists of the following:

  • Deep vein thrombosis (DVT), with or without PE
  • Intracardiac communication with a right-to-left shunt
  • Arterial embolism

Patients with normal hemodynamics and a patent foramen ovale (PFO) show no detectable abnormality in their medical history or on physical examination, chest roentgenography, or electrocardiography (ECG); however, patients with right atrial pressure elevated above the left atrial pressure tend to have right-to-left shunts and a predisposition to PDE. A PFO is the most frequent conduit for right-to-left shunts.

Patient symptoms can be exacerbated with Valsalva-type maneuvers, such as defecation, urination, and cough. Despite provocative maneuvers (eg, Valsalva or cough), left atrial pressure may remain higher than right atrial pressure, thereby preventing right-to-left shunting.

PDE is increasingly recognized as a cause of embolic stroke.[9] It is often a diagnosis of exclusion. DVT as an initial source of PDE must be ruled out clinically. A causative relationship exists among DVT, PFO, and ischemic neurologic events. Neurologic deficits in patients with cardiovascular events or DVT, PE, or any unexplained arterial embolism (eg, in the retinal artery, mesenteric artery, splenic artery, or renal artery) should be regarded with a high level of clinical suspicion for PDE.[10]

Symptoms associated with DVT may include the following:

  • Unilateral leg pain
  • Leg swelling – Swelling of one lower extremity is the most important clinical manifestation of lower-extremity DVT; generally, the swelling is painless; on palpation, the calf muscle is tender, and the Homan sign is present in fewer than one half of DVT cases
  • Unilateral leg redness – Redness is not seen in most cases of DVT but is almost always seen in superficial thrombophlebitis
  • A positive history of previous DVT – This is indicative because one third of all DVTs are recurrent

Symptoms associated with PE include the following:

  • Dyspnea
  • Chest pain
  • Hemoptysis
  • Syncope

Symptoms associated with embolic stroke include the following:

  • Unilateral weakness
  • Speech abnormality
  • Visual abnormality
  • Swallowing abnormality
  • Seizures

Symptoms associated with arterial embolism depend on the affected artery, which can supply any of the extremities or any of the major organs. Symptoms include the following:

  • Acute severe extremity pain
  • Paresthesia
  • Numbness
  • Skin discoloration
  • Inability to use the extremity

In the classic case of embolic occlusion of a lower-extremity artery (eg, the femoral or popliteal artery), the clinical picture can be summarized as the five Ps—that is, pain, pallor, pulselessness, paresthesia, and paralysis.

The clinical symptoms associated with multiorgan arterial embolism depend on the location of the embolism (eg, retinal artery, mesenteric artery, or splenic artery).

Physical Examination

Physical manifestations of PDE are related to DVT, PE, and manifestations of peripheral or central arterial embolism.

DVT can present physically with the following:

  • Unilateral leg swelling, tenderness, warmth, and erythema
  • Palpable cord along the course of the affected veins (possible)
  • Appearance of prominent venous collaterals (may be noted)

PE may present physically with the following:

  • Tachypnea
  • Hypotension
  • Central cyanosis
  • Tachycardia
  • Low-grade fever
  • Jugular venous distention
  • Accentuated pulmonic component of the second heart sound
  • New-onset atrial fibrillation (sometimes a subtle sign of PE)

Physical manifestations of cerebral embolism include the following:

  • Focal neurologic deficits that correspond to the areas of the cerebral cortex supplied by the affected artery
  • Facial weakness and visual neglect
  • Broca or Wernicke aphasia

Physical manifestations of acute arterial occlusion depend on the site, duration, and severity of the obstruction. They may include the following:

  • Pain
  • Coldness
  • Paralysis or motor weakness
  • Peripheral cyanosis or pallor
  • Loss of sensation

Intracardiac clot can lead to a new murmur, depending on the size and the location.


Complications of PDE include the following:

  • Neurologic deficit as a manifestation of stroke
  • Hemiplegia
  • Amaurosis fugax with eventual blindness
  • Motor aphasia
  • Seizure disorder complicating a cerebral insult
  • Arrhythmia, such as ventricular tachycardia or fibrillation (in cases of impending PDE)
  • Acute myocardial infarction (AMI) [11]
  • Loss of limb function with amputation
  • Organ damage (eg, renal infarction [12] )
  • Death


Diagnostic Considerations

Paradoxical embolism (PDE) is a diagnosis of exclusion. It is easily mimicked by other diseases causing cerebral and peripheral arterial embolism. The major difference is that thrombus forms on the left side of the heart, including the atrial or ventricular wall and the mitral or aortic valve. The arterial embolism may lead to permanent damage, resulting in stroke, infarction of organs, or gangrene of extremities (commonly the lower extremities).

Cardioembolism causes approximately 15% of all strokes.

PDE plays a causative role in the etiology of cerebral embolism; other causes include atrial fibrillation, ischemic cardiomyopathy, myocardial infarction (MI), mitral stenosis with or without atrial fibrillation, prosthetic valves, septic endocarditis, atrial myxoma, fat emboli, septal aneurysm, and ascending aortic atherosclerosis.

Peripheral arterial embolism from PDE must be differentiated from embolism of unknown origin. PDE may be associated with a hypercoagulable state, carcinoma (eg, of the pancreas), factor C or S deficiency, factor V Leiden (resistance to activated protein C), and prothrombin mutations. Atherothrombotic arterial manifestations may be difficult to differentiate in the process of trying to rule out the source of the embolus.

The arterial embolism may fragment or lyse, and the circulation may be restored over a period of time or immediately, mimicking a transient ischemic attack (TIA) from a different source. TIA may be a warning sign of eventual permanent neurologic damage.

Current diagnosis of PDE requires the following criteria:

  • Deep vein thrombosis (DVT), with or without pulmonary embolism (PE)
  • Abnormal communication between the right (venous) and left (systemic) sides of the circulatory system
  • Clinical, angiographic, or pathologic evidence of systemic embolism
  • Presence of a favorable pressure gradient promoting right-to-left shunting

When a patent foramen ovale (PFO) is detected in a patient with embolism, leg DVT is present in approximately 90%. DVT may be occult upon physical examination.

Because PDE is a diagnostic challenge that is prone to misdiagnosis, medicolegal action by the patient and family may result. To avoid unwanted medicolegal implications, the index of suspicion for PDE should be high.

Differential Diagnoses

  • Deep Venous Thrombosis



Laboratory Studies

Laboratory studies in paradoxical embolism (PDE) are performed to evaluate for hypercoagulable states that increase the risk of deep vein thrombosis (DVT). Younger patients (eg, < 50 years) have a higher percentage of congenital abnormalities, and testing may be warranted after the first DVT episode. As a general rule and recommendation, order blood tests after a recurrent DVT episode.

The prothrombin time (PT), the international normalized ratio (INR), and the activated partial thromboplastin time (aPTT) should be determined before anticoagulation commences. A complete blood count (CBC) should be performed; the platelet count affects the decision as to whether heparin use is plausible in the presence of thrombocytopenia.

Factor V Leiden assay determines the level of hypercoagulability. Protein C and S antigen levels may still be obtainable. Measuring protein C, protein S, and antithrombin deficiencies helps assess hypercoagulability states. Protein C and S are affected by warfarin, and antithrombin III is affected by heparin. The labs now can run a hypercoagulation panel on patients taking warfarin, but the clinician must tell the lab about the warfarin.

Prothrombin gene mutation, homocysteine levels, and antiphospholipid antibodies may not be affected by anticoagulation. A prothrombin gene mutation assay evaluates genetic risk factors for thrombus formation. Obtain homocysteine levels to exclude elevation. Lupus anticoagulant, anticardiolipin antibodies, and syphilis serology should be evaluated in patients in a prothrombotic state.

Pulmonary embolism (PE) is present in most reported cases of PDE; acute PE generally is considered a prerequisite for PDE. The quantitative plasma D-dimer enzyme-linked immunosorbent assay (ELISA) is elevated (>500 ng/mL) in more than 90% of patients with PE.

Arterial blood gas determinations evaluate the partial pressures of oxygen and carbon dioxide. This also indicates the metabolic state of the patient and provides an estimation of the alveolar-arterial oxygen gradient.

Imaging Studies for Venous Thromboembolism

DVT as an initial source of PDE must be excluded clinically and investigated with noninvasive studies such as duplex venous ultrasonography (B-mode [two-dimensional] imaging and pulse-wave Doppler interrogation) with compression studies to evaluate thrombus either through direct visualization or through inference when the vein does not collapse. Flow abnormalities occur when DVT is present. Impedance plethysmography is less sensitive for diagnosing DVT of the calves.

Magnetic resonance imaging (MRI) is another noninvasive means of detecting DVT. It is an accurate method in patients with suspected thrombosis of the superior and inferior venae cavae or pelvic veins.

Patients presenting with unilateral limb swelling whose duplex scan findings are negative for femoral or popliteal vein DVT should undergo computed tomography (CT) with intravenous (IV) contrast or magnetic resonance venography to rule out iliac vein thrombosis. DVT can be diagnosed by means of venography using contrast medium to highlight filling defects in the deep venous system.

PE imaging studies are important in PDE because of the association between PE and PDE. Findings from chest roentgenography are normal or near-normal. Abnormalities may include focal oligemia, a peripheral wedge-shaped density above the diaphragm, and an enlarged right descending pulmonary artery.

Ventilation-perfusion lung scanning is the main test for the diagnosis of PE. A high-probability scan for PE is defined as one that shows two or more perfusion defects despite normal ventilation.

Spiral CT with IV contrast is used commonly to help diagnose PE. Its sensitivity is close to that of pulmonary angiography, which is the most specific test available for the diagnosis of PE and is capable of detecting emboli as small as 1 mm. The drawback of pulmonary angiography is that it is an invasive study and therefore poses a greater risk to the patient.

Ultrasonography of Heart and Head

Contrast echocardiography has evolved as the diagnostic method of choice for the assessment of patent foramen ovale (PFO) because of its ability to visualize the atria, the interatrial septum, and the site of contrast passage. Two approaches are employed: transthoracic echocardiography (TTE) and contrast transesophageal echocardiography (TEE).

Contrast TEE is minimally invasive, involving the use of a modified gastroscope that is passed blindly into the esophagus. The nearness of the esophagus to the posterior heart and the use of higher-frequency imaging transducers allow enhanced spatial resolution and detection of intracardiac thrombi, PFO, and spontaneous left atrial echo contrast, which is the most common TEE finding among patients being evaluated for intracardiac thrombus as a source of embolism.

TEE is superior to TTE for detecting intracardiac masses and PFO. On echocardiography, an intracardiac thrombus appears as a mobile mass of irregular, serpentine, or lobulated shape, the configuration of which changes with each cardiac cycle. TTE is limited in its capability to differentiate between an intracardiac thrombus and a myxoma. Contrast TEE is more sensitive in detecting PFO (100% vs 63%) and has similar specificity (~78%). Contrast TEE has 100% sensitivity and 99% specificity for diagnosis of intracardiac thrombus.

The cough test is superior to the Valsalva maneuver in the diagnosis of PFO during contrast TEE or contrast TTE. Valsalva maneuvers cause the right atrial pressure to exceed the left atrial pressure transiently, thereby reversing the normal left-to-right gradient that keeps the flap closed. By increasing the right atrial pressure, a Valsalva maneuver or cough could potentially dislodge an entrapped thrombus. Impending PDE may result in a false-negative result on contrast echocardiography because of thrombotic occlusion of the PFO.

Bubble-contrast studies can help assess and exclude the diagnosis of PDE. A positive result from the contrast study for a PFO occurs when two to five microbubbles measuring 3-5 µm pass the interatrial septum within three cycles of complete opacification of the right atrium.

Second harmonic imaging (SHI) is a newer modality based on the system of receiving double the emitted ultrasound frequency. It improves visualization of the left-heart echocardiographic contrast agents and enhances transthoracic two-dimensional (2D) image quality. TEE and TTE with SHI in combination with IV contrast have comparable yields for the detection of atrial right-to-right shunting. In young stroke patients without clinical evidence of cardiac disease or arrhythmia in whom TEE is indicated, noninvasive TTE with SHI is a reasonable diagnostic alternative.

Transcranial Doppler ultrasonography (TCD) employs monitoring of right middle cerebral artery blood flow using a microbubble contrast medium. It is performed with the Doppler probe placed against the side of the skull just above the zygomatic arch. The sensitivity and specificity of TCD are close to 100%. This test is an alternative to TEE in the detection of right-to-left shunting.[13]

Other Tests

PDE can often be classified as proven if a venothrombus is found within an intracardiac defect, usually a PFO, at autopsy. Impending PDE has been described before death and at autopsy.

In PE, electrocardiography (ECG) may demonstrate classic findings, which include sinus tachycardia, right axis deviation, and T-wave inversion in leads V1 through V3, reflecting right ventricular strain. In PE, especially impending PDE, ECG changes may involve ventricular tachycardia or fibrillation, leading to cardiac arrest.

Noncontrast CT scans of the head are important in the evaluation of any intracranial bleeding, space-occupying lesions, midline shifts, or herniation, all of which are contraindications for treatment with thrombolytics and anticoagulation.

Intracardiac shunts can be demonstrated with right-heart catheterization by using atrial pressure gradients, typical oxygen saturation (oxygen step-up), and visual evidence of contrast medium traversing the abnormal communication with cough or Valsalva enhancement.

Evaluation of peripheral arterial embolism depends on the site that is involved (eg, the mesenteric, splenic, or renal artery). Tests employed may include mesenteric, renal, and peripheral studies or magnetic resonance angiography (MRA).



Approach Considerations

Treatment of paradoxical embolism (PDE) involves medical intervention, surgical intervention, or both. The presence of PDE in association with pulmonary embolism (PE) or atrial clots increases mortality. No difference in survival exists between patients treated medically and those treated surgically.[14]

The initial treatment is anticoagulation to prevent propagation of an intracardiac clot. Drugs used to treat PDE include the following:

  • Anticoagulants (eg, heparin, warfarin, enoxaparin, and tinzaparin)
  • Antiplatelet agents (eg, dipyridamole-aspirin, clopidogrel, and ticlopidine)
  • Thrombolytics (eg, alteplase, streptokinase, and reteplase)

Embolectomy and closure of an intracardiac communication (eg, a patent foramen ovale [PFO] or an atrial septal defect [ASD]) are the surgical treatments of choice and are widely used in patients with presumed PDE.[15, 4]

In the presence of hemodynamic compromise, patients with PDE may be transferred to medical or surgical intensive care units (ICUs). Transfer to a subacute rehabilitation facility may be beneficial in patients with significant neurologic deficits and no further risk of embolism.

Special concerns

PDE is rare in pregnancy but may occur as a consequence of the increased risk of deep vein thrombosis (DVT). Noninvasive modalities should be chosen over an invasive workup, and the treatment is mainly conservative in nature. Heparin is the anticoagulant of choice; the other anticoagulants and thrombolytics are contraindicated. The eventual treatment of choice depends on the trimester of the pregnancy and the assessment of risks versus benefits of treatment.

PDE in elderly patients is significant because of the associated morbidity and mortality in this age group. Noninvasive and less invasive procedures may be preferable. The risk of falls in elderly persons may make inferior vena cava (IVC) interruption a better choice than warfarin for long-term anticoagulation when DVT and PE are present in PDE.

Pharmacologic Therapy

Anticoagulation can be accomplished by giving heparin, a low-molecular-weight heparin (LMWH) such as enoxaparin or tinzaparin, or a direct thrombin inhibitor such as hirudin in the presence of heparin-induced thrombocytopenia (HIT). The main goal is to prevent the progression of embolic phenomena while awaiting emergency intracardiac embolectomy with PFO closure.

Thrombolysis is an alternative therapy that may be useful when acute cor pulmonale or hemodynamic instability is present because of acute PE. Anticoagulants and thrombolytics can be administered either in conjunction or separately, depending on the absence of contraindications, and they may be used as an alternative to surgical intervention if the patient refuses surgery. Available thrombolytics include alteplase (tissue plasminogen activator [tPA]), reteplase, tenecteplase, and streptokinase.

Contraindications include intracranial disease, recent surgery, and trauma. The use of tPA is associated with a roughly 1% risk of intracranial hemorrhage (ICH). It has the additional advantage of treating associated PE and acute arterial occlusion of the extremities. This can lead to immediate decrease in pulmonary artery pressure and can reduce the incidence of recurrent PDE. Treatment of the underlying cause of increased right atrial pressure is intended to reverse the right-to-left shunt, restoring the hemodynamic homeostasis.

DVT and PE in conjunction with PDE can be treated with long-term anticoagulation in the form of warfarin when surgical intervention is not an option. IVC interruption with a caval filter (eg, a Greenfield filter) can be used; however, this approach is not protective against emboli smaller than 3 mm.

If anticoagulation is contraindicated, antiplatelet therapy may be beneficial. Options include dipyridamole-aspirin, clopidogrel, dipyridamole, and ticlopidine. These agents are also beneficial in the treatment of transient ischemic attacks (TIAs), which can be a presentation of PDE.

Oxygen therapy is indicated for hypoxia.

Embolectomy and Closure of Intracardiac Communication

Surgical embolectomy with closure of a PFO or ASD appears to be the best treatment option for patients with impending PDE, except for those with fixed pulmonary hypertension, in whom indefinite anticoagulation is an acceptable option. Transcatheter closure of the intracardiac communication is an alternative to surgical closure.[16, 17, 18] It can be accomplished with the ClamShell (C. R. Bard, Murray Hill, NJ) septal occluder device, the buttoned device, or the CardioSEAL (Nitinol Medical Technologies, Boston, MA) septal occluder device.

Both surgical closure and long-term anticoagulation are associated with significant morbidity and mortality, making transcatheter closure of a PFO or an ASD a promising alternative to surgical closure and a promising treatment for patients who are unable to tolerate long-term anticoagulation or who are poor surgical candidates.

Complications of nonsurgical closure of a PFO or ASD for PDE include the intermediate-term risks of recurrent neurologic events due to suboptimal device performance resulting from malalignment, with significant residual shunting and the development of a displaced fractured device-arm friction lesion. The annual rate of recurrent stroke or a transient neurologic event after device placement is 3.2%.

Monitoring of patients is achieved with postclosure transesophageal echocardiography (TEE) or transthoracic echocardiography (TTE) using Doppler color mapping or an agitated saline solution contrast injection. Residual shunting may eventually lead to surgical closure when recurrent neurologic deficit or stroke complicates transcatheter PFO or ASD closure.

There has been debate regarding how best to manage patients with PFO after a cryptogenic stroke. A meta-analysis by Abdelaziz et al aimed at assessing long-term outcomes of transcatheter PFO closure versus medical therapy alone found that the former reduced the recurrence of stroke as compared with the latter and that no significant safety concerns arose.[19]  

A review of eight randomized controlled trials (RCTs) by Fortuni et al found that patients treated with PFO closure were less likely to experience recurrence of cerebrovascular events than those treated medically; however, PFO closure was associated with a higher incidence of new-onset atrial fibrillation or flutter.[20]

A meta-analysis of five RCTs by Darmoch et al, comparing PFO closure with medical therapy in patients with cryptogenic stroke, found that PFO closure was a safe and effective intervention for prevention of stroke recurrence.[21]



Appropriate treatment can lead to morbidity and mortality. Thrombolytic treatment can lead to ICH with extensive neurologic deficits. Transcatheter closure of PFO may lead to residual shunting as a result of malalignment of the occluder device; this can cause recurrent strokes.

Surgical intervention (in the form of embolectomy and PFO closure) in the presence of intracardiac embolus and PFO has a survival rate of 75% and a mortality close to 25%. In view of all the complications of treatment, the benefits must be carefully weighed against the risks. To avoid medicolegal pitfalls, patients and their families should be provided with a thorough explanation of the outcome of the intervention.


The diet depends on whether the patient has any significant comorbid conditions (eg, hypertension or diabetes mellitus) and whether he or she is stable enough to tolerate oral feeding or assisted feeding. Nasogastric or nasoenteral feeding is appropriate when patients cannot protect the airway.


Patients with PDE should remain in bed until the threat of dislodgment of the thrombus is minimal. Elderly patients who have an increased risk of falls or patients who are confused should be protected with restraints or one-on-one monitoring to prevent falls that can lead to bleeding in the presence of anticoagulation. Early mobilization is possible in patients who are hemodynamically stable and are not at risk for falls or further embolism.


Prevention has been controversial. Whether prophylaxis benefits persons with a recognized predisposition for PDE and whether routine screening for PFO or ASD with contrast echocardiography is advisable for patients with hypercoagulable states are yet to be determined.


Radiologic interventionists can help in the diagnostic evaluation of patients with PDE (which may include angiographic or arteriographic studies); they can also help in the treatment of these patients with transcatheter device placement for PFO closure.

For removal of an intracardiac thrombus to correct impending PDE, a cardiothoracic surgeon should be consulted. Open-heart surgery is an alternative for closing the intracardiac communication.

For peripheral embolectomy, a vascular surgeon should be consulted. All emboli removed from the peripheral arterial system should be sent to the pathology laboratory for histologic examination; cardiac myxoma is an important differential diagnosis of PDE, and the clinical manifestations (peripheral, visceral, and cerebral embolism) are identical.

For patients with PDE and PE with hemodynamic compromise, consultation with a pulmonologist or an intensivist may be useful with respect to positive-pressure ventilation and intensive care monitoring.

Early (ie, ≤ 1 hour) evaluation by a neurologist is very important when thrombolysis is to be performed in the setting of acute stroke.

Long-Term Monitoring

Inpatient care for people with PDE depends on their hemodynamic stability and on the any associated presenting clinical manifestations (eg, PE, TIA, acute arterial embolism, or debilitating neurologic deficits) that may warrant intensive care or regular monitoring. Safety precautions and fall prevention measures must be initiated as indicated, especially in elderly patients.

Aspiration prophylaxis is paramount in patients who are bedridden and have minimal or no cough reflex. A neurologic watch is necessary to monitor any further neurologic deficit, so that intervention can take place before further deterioration. Intensive care monitoring is needed when hypotension is present when the patient needs vasopressors, intubation, and mechanical ventilation.

Pain management is needed in patients with acute arterial limb occlusion that commonly presents with severe pain and pain associated with DVT. Gastrointestinal prophylaxis is needed to prevent stress ulcers in the presence of cerebral insult. Skin care may involve frequent turning and protective skin devices to prevent skin breakdown and eventual decubitus ulcer.

Outpatient care for PDE is based on evidence of idiopathic venous thrombosis, hypercoagulable states, PE, risk-determined DVT, and the sequelae of the clinical manifestation.

Long-term anticoagulation with warfarin may be used for 6 months in patients with DVT or PE or as lifelong therapy with monitoring of the international normalized ratio (INR) in patients with hypercoagulable states. Long-term antithrombotic therapy with antiplatelet drugs is needed for patients with a history of TIA.

Physical therapy is needed for patients who will benefit from physical rehabilitation. A visiting nurse may be highly beneficial for monitoring INR at home and helping patients in the administration of subcutaneous injection of LMWH used for long-term anticoagulation, with the goal of eventual self-administration.



Medication Summary

Pharmacologic treatment of paradoxical embolism (PDE) is based on anticoagulation to prevent clot propagation. Anticoagulants, including heparin and low-molecular-weight heparins (LMWHs) such as enoxaparin and tinzaparin, are used for acute cases. The direct thrombin inhibitor lepirudin is used in patients with heparin-induced thrombocytopenia (HIT). The dosages of all of these medications are adjusted in patients with compromised renal states. Warfarin is used for long-term anticoagulation over a period of months.

Thrombolytics are used commonly to lyse a clot in patients with acute arterial occlusion, preventing permanent damage such as occurs in ischemic stroke, pulmonary embolism (PE), and arterial occlusion. Dosages for thrombolytics vary, depending on the site involved.

Anticoagulants, Hematologic

Class Summary

Anticoagulants are used for the treatment of thromboembolic disorders.


Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse clot but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.

Enoxaparin (Lovenox)

Enoxaparin enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases inhibition of factor Xa. The average duration of treatment is 7-14 days.

Desirudin (Iprivask)

Desirudin is a highly selective thrombin inhibitor. It inhibits fibrin formation, activation of coagulation factors, and thrombin-induced platelet aggregation. This results in prolongation of the activated partial thromboplastin time.

Warfarin (Coumadin, Jantoven)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders. Tailor the dose to keep the international normalized ratio (INR) in the range of 2-3 with an overlap of 3-5 days of a therapeutic activated partial thromboplastin time (aPTT) using the heparin regimen previously described.

Lepirudin (Refludan)

Lepirudin, a recombinant hirudin derived from yeast cells, is a highly specific direct thrombin inhibitor. It is indicated for anticoagulation in HIT and associated thromboembolic disease. Its action is independent of antithrombin III. Lepirudin blocks the thrombogenic activity of thrombin. It affects all thrombin-dependent coagulation assays (eg, aPTT values increase in a dose-dependent manner). Adjust the dose on the basis of aPTT ratios (target, 1.5-2.5 times normal) determined every 4 hours and then daily.

Argatroban (Acova)

Argatroban is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. It inhibits thrombin-induced platelet aggregation. It is used when heparin cannot be used, as in the case of heparin-induced thrombocytopenia or heparin allergy. This drug is given intravenously. The initial dose is 2 mcg/kg/min as a constant infusion. Prothrombin time should be monitored, with the goal of 1.5-3 times normal, not to exceed 100 sec. The maintenance dose should not exceed 10 mcg/kg/min. When warfarin therapy is initiated in patients receiving argatroban, note that argatroban increases international normalized ratio values. For pediatric patients, the initial dose is 0.75 mcg/kg/min and the maintenance dose is adjusted in increments of 0.1-0.25 mcg/kg/min to maintain a prothrombin time of 1.5-2 sec.

Dabigatran (Pradaxa)

Dabigatran etexilate is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. It inhibits thrombin-induced platelet aggregation. The dose is 150 mg orally twice daily. No blood tests are needed.


Class Summary

Thrombolytic agents are used to restore circulation through a previously occluded vessel by bringing about rapid and complete removal of a pathologic intraluminal thrombus or embolus that has not been dissolved by the endogenous fibrinolytic system.

Alteplase (Activase)

Alteplase is a tissue plasminogen activator (tPA) used in the management of acute myocardial infarction (AMI), acute ischemic stroke (AIS), and pulmonary embolism (PE). Its safety and efficacy with concomitant administration of heparin or aspirin during the first 24 hours after symptom onset have not been investigated.

Streptokinase (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.

Reteplase (Retavase)

Reteplase is a recombinant tPA that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, it has been shown to be comparable with tPA in achieving patency at 90 minutes. Heparin and aspirin are usually given concomitantly and afterwards.

Tenecteplase (TNKase)

Tenecteplase is a modified version of alteplase that is made by substituting 3 amino acids. It has a longer half-life than alteplase and thus can be given as a single bolus infused over 5 seconds (as opposed to the 90 minutes required for alteplase). It appears to cause less non–intracranial bleeding than alteplase but carries a comparable risk of intracranial bleeding and stroke.

Base the dose on the patient's weight. Initiate treatment as soon as possible after the onset of AMI symptoms. Because tenecteplase contains no antibacterial preservatives, it must be reconstituted immediately before use.

Antiplatelet Agents, Cardiovascular

Class Summary

Antiplatelet agents inhibit platelet aggregation and reduce thrombotic stroke in transient ischemia of the brain.

Clopidogrel (Plavix)

Clopidogrel selectively inhibits adenosine diphosphate (ADP) binding to platelet receptors and subsequent ADP-mediated activation of the glycoprotein (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation.


Ticlopidine is second-line antiplatelet therapy for patients in whom aspirin is not tolerated or is ineffective.

Dipyridamole 200 mg/aspirin 25 mg (Aggrenox)

Dipyridamole-aspirin is a combination antiplatelet agent that takes advantage of the additive antiplatelet effects of the 2 drugs. Dipyridamole acts via the adenosine-platelet A2-receptor system, whereas aspirin inhibits platelet aggregation by causing irreversible inhibition of cyclooxygenase system, thereby reducing generation of thromboxane A2, a powerful enhancer of platelet aggregation and vasoconstriction.