AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1877, Cohnheim initially described the term paradoxical embolism (PDE). It illustrates a condition in which emboli from the venous system reach the systemic arterial circulation by passing through an abnormal communication between the chambers of the heart, leading to a systemic manifestation such as stroke, kidney infarction, or acute limb infarction.

Zahn reported a case in 1885 in which autopsy revealed thrombosis in the pelvic veins, multiple systemic emboli, and a thrombus passing through a patent foramen ovale (PFO).

The clinical manifestations of PDE are nonspecific, and the diagnosis is difficult to establish. Patients with PDE may present with neurological abnormalities or features suggesting arterial embolism. The disease starts with the formation of emboli within the venous system, which traverse a PFO into the systemic circulation. 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. Septic emboli have led to brain abscesses. Projectile embolization is rare (eg, from a shotgun pellet).

The management of PDE is both medical and surgical in nature. PDE is considered the major cause of cerebral ischemic events in young patients. PDE rarely may occlude the pelvic aortic bifurcation. The largest documented thrombus in a PFO (impending PDE) was 25 cm in length.

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

Pathophysiology

PDE originates from a venous thrombosis. 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.

Many conditions predispose individuals to increased risk for development of venous thrombosis, including hypercoagulable states, such as factor V Leiden (resistance to activated protein C); antithrombin III, protein C, or protein S deficiencies; antiphospholipid antibody syndrome; prothrombin mutation; and dysfibrinogenemia.

Immobilization, pregnancy, estrogen use, previous DVT, trauma, and neoplasms (ie, breast, pelvic malignancy, stomach, pancreas, lung) are risk factors. Surgery also is a common risk factor for DVT, especially orthopedic, abdominal, and genitourinary procedures. Thromboangiitis obliterans and homocystinuria, 2 types of venulitis, are among the least common risk factors. The thrombus is composed of platelets, fibrin, and, eventually, red blood cells. The thrombus tends to propagate in the direction of the blood flow.

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

A PFO is defined as a valvelike opening between the septum primum and the septum secundum without evidence of an anatomic defect in the septa. PFO is significant in the etiology of PDE if associated right-to-left shunting is present. Some causes of right-to-left shunting are 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 of the right side of the heart; and 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, resulting 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.

Frequency

United States

The actual frequency of PDE is unknown 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). PFO prevalence is approximately 20-30% in 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.

Mortality/Morbidity

• Morbidity and mortality are increased in patients with PDE and PE, depending on the size of the embolus and end-organ lodgment.
• Patients with PDE can have permanent neurological damage with residual physical incapability.

Race

• No established differences exist across racial or ethnic groups.

Sex

• Both sexes are represented equally in the demographics of the disease because no sex difference exists in the incidence of PFO in the normal population.

Age

• Elderly patients are commonly affected. Risk of DVT is increased in the elderly population. This correlates to 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 in this age group usually is larger when compared to 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 shunt is the most frequent cardiac finding in patients younger than 55 years with an otherwise unexplained ischemic cerebral insult or cryptogenic stroke.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical findings of PDE are nonspecific and are related to other disease entities such as PE, neurological deficits associated with transient ischemic attack (TIA)/embolic stroke, and systemic arterial embolism.

The clinical triad of PDE is DVT with or without PE, intracardiac communication with a right-to-left shunt, and arterial embolism. Patients with normal hemodynamics and a PFO show no detectable abnormality in their medical history or on their physical examination findings, chest roentgenogram, or ECGs; however, patients with right atrial pressure elevated above the left atrial pressure tend to have right-to-left shunts and a predisposition to PDE. PFO is the most frequent conduit for right-to-left shunts in more than 70% of cases.

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 has been recognized increasingly as a cause of embolic stroke. It often is 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. Neurological deficits in patients with cardiovascular events or DVT, PE, or any unexplained arterial embolism, such as in the retinal artery, mesenteric artery, splenic artery, and renal artery, should be regarded with a high level of clinical suspicion for PDE.

• 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, it is painless swelling. On palpation, the calf muscle is tender, and the Homan sign is present in less than half the cases of DVT.)
  • Unilateral leg redness (Redness is not seen in most cases of DVT. It is almost always seen in superficial thrombophlebitis.)
  • A positive history of previous DVT (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
  • In the classic case of embolic occlusion of lower extremity artery (eg, femoral or popliteal artery), the clinical picture can be described as 5 Ps: pain, pallor, pulselessness, paresthesia, and paralysis.
  • Paresthesia
  • Numbness
  • Skin discoloration
  • Inability to use the extremity
• Clinical symptomatology associated with multiorgan arterial embolism depends on the location of the embolism (eg, retinal artery, mesenteric artery, splenic artery).

Physical

Physical manifestations of PDE are related to DVT, PE, and manifestations of peripheral/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 following:
• • Tachypnea
  • Hypotension
  • Central cyanosis
  • Tachycardia
  • Low-grade fever
  • Jugular venous distension
  • Accentuated pulmonic component of the second heart sound
  • Newly 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 that the affected artery supplies
  • 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. Manifestations include the following:
• • Pain
  • Coldness
  • Paralysis/motor weakness
  • Peripheral cyanosis or pallor
  • Loss of sensation
• Intracardiac clot can lead to a new murmur, depending on the size and the location.

Causes

• Many conditions predispose individuals to increased risk for DVT. These can include 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 (ie, breast, pelvic malignancy, stomach)
  • Surgery and/or procedures such as pancreas and lung surgeries
  • Orthopedic, abdominal, and genitourinary procedures
  • Trauma
  • Venulitis such as thromboangiitis obliterans and homocystinuria
• Intracardiac communication of the venous and arterial circulations can lead to PDE, and this communication can occur via the following:
• • PFO
  • ASD
  • Pulmonary arteriovenous malformation
  • Ventricular septal defect
  • Ebstein anomaly
  • Patent ductus arteriosus

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

PDE is a diagnosis of exclusion. Other diseases causing cerebral and peripheral arterial embolisms easily mimic PDE. 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, 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 an embolism of unknown source. PDE may be associated with a hypercoagulable state, carcinoma (eg, pancreatic), factor C or S deficiency, factor V Leiden (resistance to activated protein C), and prothrombin mutations. Atherothrombotic arterial manifestations may be difficult to differentiate when 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 TIA from a different source. TIA may be a warning sign for eventual permanent neurological damage.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Current diagnosis of PDE requires the following criteria:
• • DVT with or without PE
  • Abnormal communication between right (venous) and left (systemic) circulation
  • Clinical, angiographic, or pathologic evidence for systemic embolism
  • Presence of a favorable pressure gradient, promoting right-to-left shunting
• When a PFO is detected in a patient with embolism, leg DVT is present in approximately 90%. DVT may be occult upon physical examination.
• The laboratory studies in PDE are performed to evaluate for hypercoagulability that increases the risk of DVT. Younger patients (eg, <50 y) 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. For more information, see Deep Venous Thrombosis.
• Perform measurements of prothrombin time, International Normalized Ratio (INR), and activated partial thromboplastin time before anticoagulation commences.
• CBC count assesses the platelet count to decide whether heparin use is plausible in the presence of thrombocytopenia.
• Factor V Leiden assay determines the level of hypercoagulability.
• Protein C and S activity are affected by warfarin (coumadin). Protein C and S antigen levels still may be obtainable.
• Obtain homocysteine levels to exclude elevation.
• Lupus anticoagulant, anticardiolipin antibodies, and syphilis serology should be evaluated in patients in a prothrombotic state.
• Measuring protein C, protein S, and antithrombin deficiencies helps assess hypercoagulability states.
• A prothrombin gene mutation assay evaluates genetic risk factors for thrombus formation.
• 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 is elevated (>500 ng/mL) in more than 90% of patients with PE.
• Protein C and S are affected by coumadin, and antithrombin III is affected by heparin. The labs now can run a hypercoagulation panel on patients taking coumadin, but the clinician must tell the lab about the coumadin.
• Prothrombin gene mutation, homocysteine levels, and antiphospholipid antibodies may not be affected by anticoagulation.

Imaging Studies

• DVT as an initial source of PDE must be excluded clinically and investigated with noninvasive studies such as duplex venous ultrasonography (B-mode [2-dimensional] imaging and pulse-wave Doppler interrogation) with compression studies to evaluate thrombus either by direct visualization or by 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.
  • MRI is another noninvasive means to detect DVT. It is used accurately in patients with suspected thrombosis of the superior and inferior venae cavae or pelvic veins.
  • Patients who present with unilateral limb swelling whose duplex scan findings are negative for femoral or popliteal vein DVT should undergo CT scan with intravenous contrast or MR venogram to rule out iliac vein thrombosis.
• Contrast echocardiography has evolved as the diagnostic method of choice for the assessment of PFO in view of direct visualization of the atria, atrial septum, and the site of contrast passage. PFO can be detected using contrast echocardiography that includes contrast transthoracic echocardiogram (TTE) and contrast transesophageal echocardiogram (TEE).
• • TEE is minimally invasive, involving 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 allows 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 in detecting intracardiac masses and PFO. The echocardiographic characteristics of an intracardiac thrombus are those of 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 than contrast TTE in detecting PFO (100% vs 63%) and has similar specificity at approximately 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 be greater than the left atrial pressure transiently, thereby reversing the normal left-to-right gradient that keeps the flap closed. Valsalva or cough could potentially dislodge an entrapped thrombus because of increased right atrial pressure. 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 qualitatively. A positive result from the contrast study for a PFO occurs when 2-5 microbubbles measuring 3-5 micrometer pass the interatrial septum within 3 cycles of complete opacification of the right atrium.
• Second harmonic imaging (SHI) is a new imaging modality that is based on the system of receiving double the emitted ultrasound frequency. It has been demonstrated to improve the visualization of the left heart echo-contrast agents and to improve transthoracic 2-dimensional image quality. TEE and TTE with SHI in combination with intravenous contrast have a comparable yield for the detection of atrial right-to-right shunt. In young patients with stroke without clinical evidence of cardiac disease or arrhythmia in whom TEE is indicated, the noninvasive TTE with SHI is a reasonable diagnostic alternative.
• Transcranial Doppler ultrasonography (TCD) employs monitoring of right-middle cerebral artery blood flow using microbubble contrast medium. Perform TCD with the Doppler probe placed against the side of the skull just above the zygomatic arch. Sensitivity and specificity are close to 100%. This is an alternative to TEE in the detection of right-to-left shunting.
• PE imaging studies are important in PDE because of the association between PE and PDE.
• • Chest roentgenogram findings are normal or near normal. Abnormalities include focal oligemia, a peripheral wedge-shaped density above the diaphragm, or an enlarged right descending pulmonary artery.
  • Ventilation and perfusion lung scanning is the main test for the diagnosis of PE. A high-probability scan for PE is defined as having 2 or more perfusion defects despite normal ventilation.
  • Spiral computed tomography (CT) scan with intravenous contrast is used commonly to help diagnose PE. It has sensitivity close to that of pulmonary angiography, which has been the criterion standard for PE.
• Noncontrast CT scans of the head are important in evaluating any intracranial bleeding, space-occupying lesions, midline shifts, or herniation, which are contraindications to treatment with thrombolytics and anticoagulation.

Other Tests

• 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.
• PDE often can be classified as proven if a venothrombus is found within an intracardiac defect, usually a PFO, at autopsy. Impending PDE has been described prior to death and at autopsy.
• ECG may demonstrate classic findings in PE, which include sinus tachycardia, right axis deviation, and T-wave inversion in leads V₁ through V₃, reflecting right ventricular strain.
• ECG changes in PDE may involve ventricular tachycardia or fibrillation, leading to cardiac arrest, especially in impending PDE.

Procedures

• Venography: DVT can be diagnosed using venography, using contrast medium to highlight filling defects in the deep venous system.
• Cardiac catheterization: Intracardiac shunts can be demonstrated by 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.
• Pulmonary angiography: This is the most specific test available for the diagnosis of PE, and it can detect emboli as small as 1 mm. The drawback is that it is an invasive study, therefore conferring a greater risk to the patient.
• Peripheral arterial embolisms are evaluated depending on the site that is involved (ie, mesenteric, splenic, renal). Angiographic/arteriographic studies include mesenteric, renal, and peripheral studies or magnetic resonance angiography.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

PDE treatment involves medical intervention, surgical intervention, or both. The initial treatment is anticoagulation to prevent propagation of an intracardiac clot. The presence of PDE with PE or atrial clots increases mortality. No difference in survival exists whether patients are treated medically or surgically.

• Anticoagulation can be in the form of heparin, low molecular-weight heparin (LMWH; eg, enoxaparin, tinzaparin), or the new direct thrombin inhibitors (eg, hirudin) in the presence of heparin-induced thrombocytopenia (HIT). The main goal is to prevent the progression of embolic phenomena while awaiting emergent intracardiac embolectomy with PFO closure.
• Thrombolytics are another alternative available therapy when acute cor pulmonale or hemodynamic instability is present because of acute PE. Anticoagulation and thrombolytics can be used in conjunction or separately, depending on the absence of contraindications and as an alternative to surgical intervention if the patient refuses. Thrombolytics include the recombinant tissue-type plasminogen activator (tPA), reteplase, and TNKase.
• • Contraindications include intracranial disease, recent surgery, or trauma. An approximate 1% risk of intracranial hemorrhage exists with the use of tPA.
  • 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. Inferior vena cava interruption with caval filters, such as a Greenfield filter, can be used. However, they are not protective against emboli smaller than 3 mm.
• Antiplatelet therapy may be beneficial if anticoagulants are contraindicated. Options include dipyridamole/aspirin (Aggrenox), clopidogrel (Plavix), dipyridamole (Persantine), and ticlopidine (Ticlid). They also are beneficial in the treatment of TIA, which can be a presentation of PDE.
• Oxygen therapy is indicated for hypoxia.

Surgical Care

Surgical therapies that include embolectomy and intracardiac communication closure (commonly PFO) are the treatments of choice and are used widely in patients with presumed PDE.

• Surgical embolectomy with closure of a PFO or ASD appears to be the best treatment option for patients with an impending PDE, except in fixed pulmonary hypertension, where indefinite anticoagulation is an acceptable option.
• Transcatheter closure of intracardiac communication is an alternative option to surgical closure.
• • Both surgical closure and long-term anticoagulation therapy have significant associated morbidity and mortality, making transcatheter closure of PFO or 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.
  • Transcatheter closure can be employed using a Bard ClamShell septal occluder device, the buttoned device, or the CardioSEAL septal occluder device. These all are available for transcatheter closure.
  • Complications of nonsurgical closure of PFO or ASD for PDE are intermediate-term risks of recurrent neurologic events due to suboptimal device performance due to malalignment of the device, with significant residual shunting and the development of a displaced fractured device-arm friction lesion. The rate of recurrent stroke or a transient neurological event following the device placement is 3.2% per year.
• Monitoring of patients is achieved with postclosure TEE or TTE using Doppler color mapping or agitated saline solution contrast injection. Residual shunting eventually may lead to surgical closure when recurrent neurologic deficit or stroke complicates transcatheter PFO or ASD closure.

Consultations

• Radiology interventionists can help in the diagnostic evaluation of patients with PDE, which may include angiographic/arteriographic studies, and in the treatment of these patients with transcatheter device placement for PFO closure.
• A cardiothoracic surgeon should be consulted to remove an intracardiac thrombus to correct impending PDE. Open-heart surgery is an alternative to close the intracardiac communication.
• A vascular surgeon should be consulted for peripheral embolectomy.
• All emboli removed from the peripheral arterial system should be sent to pathology for histological examination, since cardiac myxoma is an important differential diagnosis of PDE, and the clinical manifestations (peripheral, visceral, cerebral embolism) are identical.
• Consultation with a pulmonologist and/or intensivist may be useful for patients with PDE and PE with hemodynamic compromise for positive-pressure ventilation and intensive care monitoring.
• Early ( <1 h) evaluation by a neurologist is very important for thrombolysis in acute stroke.

Diet

• Diet depends on the comorbid state of the patient, such as hypertension or diabetes mellitus, and whether the patient is stable enough to tolerate oral feeding or assisted feeding.
• Nasogastric/nasoenteral feeding is appropriate when patients cannot protect their airway.

Activity

• Bedrest: Patients with PDE should remain in bed until the threat of dislodgement of the thrombus is minimal.
• Restraints: Elderly patients with 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, without risk of falls and without risk of further embolism.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

PDE treatment is based on anticoagulation to prevent clot propagation. Anticoagulants, such as heparin and LMWHs (ie, enoxaparin, tinzaparin), are used for acute cases. Lepirudin (direct thrombin inhibitor) is used in HIT. All medications described previously are adjusted in those 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 acute arterial occlusion, preventing permanent damage as occurs in ischemic stroke, PE, and arterial occlusion. Dosages for thrombolytics vary depending on the site involved.

Drug Category: Anticoagulants

For treatment of thromboembolic disorders.

Drug Name	Enoxaparin (Lovenox)
Description	Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d.
Adult Dose	1 mg/kg SC q12h; alternatively, 1.5 mg/kg SC qd
Pediatric Dose	Not established; suggested dose is as follows: <2 months: 0.75 mg/kg/dose SC bid >2 months: 0.5 mg/kg/dose SC bid
Contraindications	Documented hypersensitivity; major bleeding; thrombocytopenia
Interactions	Platelet inhibitors or oral anticoagulants, such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine, may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWHs; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop

Drug Name	Tinzaparin (Innohep)
Description	LMWH with antithrombotic effect. It inhibits factors Xa and IIa (thrombin). The primary inhibitory activity is mediated through antithrombin.
Adult Dose	175 IU/kg SC qd at same time each day
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active major bleeding; thrombocytopenia
Interactions	Platelet inhibitors or oral anticoagulants, such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine, may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Bleeding diathesis; uncontrolled arterial hypertension; history of recent GI ulceration, diabetic retinopathy, and hemorrhage

Drug Name	Warfarin (Coumadin)
Description	Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders. Tailor dose to maintain an INR in the range of 2-3 with an overlap of 3-5 days of therapeutic aPTT using heparin regimen as previously described.
Adult Dose	5-15 mg/d PO qd for 2-5 d; adjust dose according to desired INR
Pediatric Dose	Administer weight-based dose of 0.05-0.34 mg/kg/d PO; adjust dose according to desired INR
Contraindications	Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Interactions	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
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	Lepirudin (Refludan)
Description	Highly specific direct thrombin inhibitor. Recombinant hirudin derived from yeast cells. Indicated for anticoagulation in HIT and associated thromboembolic disease. Action is independent of antithrombin III. It blocks thrombogenic activity of thrombin. Affects all thrombin-dependent coagulation assays (ie, aPTT values increase in dose-dependent manner). Adjust dose based on aPTT ratios (target 1.5-2.5 normal) determined q4h and then qd.
Adult Dose	0.4 mg/kg (not to exceed 44 mg) slow IV bolus over 15-20 sec, then 0.15 mg/kg/h (not to exceed 16.5 mg/h) continuous IV for 2-10 d or longer as indicated
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Thrombolytics, oral anticoagulants (ie, warfarin), antiplatelet agents, penicillin, and cephalosporins may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Recent puncture of large vessels or organ biopsy, anomaly of vessels or organs, recent CVA, intracerebral surgery; severe uncontrolled hypertension; bacterial endocarditis; advanced renal impairment; recent major bleeding (ie, intracranial, GI, intraocular, pulmonary)

Drug Category: Thrombolytics

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

Drug Name	Streptokinase (Streptase)
Description	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.
Adult Dose	PE Loading dose: 250,000 IU IV over 30 min Maintenance: 100,000 IU/h IV for 24 h (if concurrent DVT suspected, administer for 72 h) DVT Loading dose: 250,000 IU IV over 30 min Maintenance: 100,000 IU/h IV for 72 h Arterial thrombosis or embolism Loading dose: 250,000 IU IV over 30 min Maintenance: 100,000 IU/h IV for 24-72 h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; active internal bleeding; intracranial neoplasm; aneurysm; diathesis; severe uncontrolled arterial hypertension
Interactions	Antifibrinolytic agents may decrease effects; heparin, warfarin, and aspirin may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in severe hypertension, IM administration of medications, trauma, or surgery in the previous 10 days; measure hematocrit, platelet count, aPTT, TT, PT, or fibrinogen levels before therapy is implemented; either TT or aPTT should be less than twice the normal control value following infusion of streptokinase and before (re) instituting heparin; do not take blood pressure in the lower extremities because it may dislodge possible deep vein thrombi; monitor PT, aPTT, TT, or fibrinogen 4 h after the initiation of therapy

Drug Name	Reteplase (Retavase)
Description	A recombinant tPA that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, has been shown to be comparable to tPA in achieving TIMI 2 or 3 patency at 90 min. Heparin and aspirin usually are given concomitantly and after.
Adult Dose	10 U IV over 2 min, followed 30 min later by a second dose at 10 U IV
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncontrolled hypertension; recent intracranial surgery; malformation of aneurysm; bleeding diathesis
Interactions	Anticoagulants and antiplatelets may increase risk of bleeding
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular arrhythmias, hypotension, and perfusion arrhythmias

Drug Name	Tenecteplase (TNKase)
Description	Modified version of alteplase (tPA) made by substituting 3 amino acids of alteplase. Has longer half-life and, thus, can be given as single bolus over 5-s infusion instead of 90 min with alteplase. Appears to cause less non–intracranial bleeding but has similar risk of intracranial bleeding and stroke as alteplase. Base dose using patient weight. Initiate treatment as soon as possible after onset of AMI symptoms. Because tenecteplase contains no antibacterial preservatives, reconstitute immediately before use.
Adult Dose	Give IV bolus over 5 s using body weight, not to exceed 50 mg <60 kg: 30 mg (6 mL) 60-70 kg: 35 mg (7 mL) 70-80 kg: 40 mg (8 mL) 80-90 kg: 45 mg (9 mL) >90 kg: 50 mg (10 mL)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active internal bleeding; intracranial neoplasm, arteriovenous malformation, or aneurysm; history of cerebrovascular accident; intracranial or intraspinal surgery or trauma within 2 months; known bleeding diathesis; severe uncontrolled hypertension
Interactions	Heparin and vitamin K antagonists, acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors may increase risk of bleeding if coadministered
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution if readministering to patients who have received prior plasminogen activator therapy (may develop immunity); coronary thrombolysis may result in arrhythmias associated with reperfusion but not different from those often seen in ordinary course of AMI (may be managed with standard antiarrhythmic measures); in elderly, weigh benefits of tenecteplase on mortality against risk of increased adverse events, including bleeding; cholesterol embolism is associated with all types of thrombolytic agents, but true incidence is unknown

Drug Category: Antiplatelets

Platelet aggregation inhibition and reduction of thrombotic stroke in transient ischemia of the brain.

Drug Name	Ticlopidine (Ticlid)
Description	Second-line antiplatelet therapy for patients who cannot tolerate or fail ASA therapy.
Adult Dose	250 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; neutropenia or thrombocytopenia; liver damage; active bleeding disorders
Interactions	Effects may decrease with coadministration of corticosteroids and antacids; toxicity increases when taken concurrently with theophylline, cimetidine, aspirin, and NSAIDS
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Discontinue if absolute neutrophil count decreases to <1200/mm3 or if platelet count falls to <80,000/mm3

Drug Name	Dipyridamole 200 mg/aspirin 25 mg (Aggrenox)
Description	Combination antiplatelet agent using additive antiplatelet effects of dipyridamole and aspirin. Dipyridamole acts via adenosine-platelet A2-receptor system, while aspirin inhibits platelet aggregation by irreversible inhibition of cyclooxygenase system and thus inhibits generation of thromboxane A2, a powerful enhancer of platelet aggregation and vasoconstriction.
Adult Dose	1 cap PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; NSAIDS allergy; asthma; rhinitis; nasal polyps; Reye syndrome; coagulation abnormalities; pregnancy (especially third trimester)
Interactions	Diminishes effects of beta-blockers, ACE inhibitors, cholinesterase inhibitors, and diuretics; increased risk of bleeding with anticoagulants, antineoplastic agents, and NSAIDs; increases effect of antidiabetic agents; increased aspirin toxicity with corticosteroids; increases toxicity of methotrexate; aspirin added to treatment regimen that includes valproic acid increases valproic acid toxicity; aspirin discontinued from treatment regimen that includes valproic acid decreases effectiveness of valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Pregnancy category D (aspirin) and B (dipyridamole); caution in coronary artery disease, hepatic insufficiency, hypotension, renal failure, recent MI, unstable angina, GI ulcers, or bleeding peptic ulcers; discontinue if dizziness or tinnitus occur

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care for people with PDE depends on their hemodynamic stability and associated presenting clinical manifestations, such as PE, TIA, acute arterial embolism, or debilitating neurological deficits, that may warrant intensive care or regular monitoring.
• • Safety precautions and fall prevention - In the presence of risk for falls and safety concerns, especially in elderly patients
  • Aspiration prophylaxis - Paramount in patients who are bedridden with minimal or no cough reflex
  • Neurologic watch - To monitor any further neurologic deficit to intervene before further deterioration
  • Intensive care monitoring - In the presence of hypotension and when the patient needs vasopressors, intubation, and mechanical ventilation
  • Pain management - In patients with acute arterial limb occlusion that commonly presents with severe pain and pain associated with DVT
  • Gastrointestinal prophylaxis - 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

Further Outpatient Care

• Outpatient care for PDE is based on evidence of idiopathic venous thrombosis, hypercoagulable states, PE, the risk-determined DVT, and the sequelae of the clinical manifestation.
• • Chronic anticoagulation therapy with warfarin - May be used for 6 months in DVT/PE or as lifelong therapy with monitoring of the INR in the presence of hypercoagulable states
  • Chronic antithrombotic therapy with antiplatelet drugs - For patients with history of TIA
  • Physical therapy - For patients who will benefit from physical rehabilitation
  • Visiting nurse - May be highly beneficial for monitoring INR at home and helping patients in the administration of subcutaneous injection of LMWH when used for long-term anticoagulation for eventual self-administration

In/Out Patient Meds

• Anticoagulation
• • Warfarin
  • Enoxaparin
  • Tinzaparin
• Antiplatelet therapy
• • Dipyridamole/aspirin (Aggrenox)
  • Clopidogrel (Plavix)
  • Ticlopidine (Ticlid)
• Thrombolytics, eg, alteplase (tPA)

Transfer

• Intensive care unit: Patients with PDE can be transferred to medical or surgical intensive care units in the presence of hemodynamic compromise.
• Subacute rehabilitation facility: This may be beneficial in patients with significant neurological deficits and with no further risk of emboli.

Deterrence/Prevention

• Prevention remains controversial. Whether or not prophylaxis of persons with a recognized predisposition for PDE is beneficial and whether patients with hypercoagulable states should be screened routinely using contrast echocardiography for PFO or ASD are not established.

Complications

• 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/fibrillation in cases of impending PDE
• Acute myocardial infarction
• Loss of limb function with amputation
• Organ damage, eg, renal infarction
• Death

Prognosis

• Prognosis of PDE is good when it is not complicated.
• Prognosis of PDE is poor when it is complicated by PE. When impending PDE occurs, the choice of treatment involves open-heart surgery.

Patient Education

• Patients on long-term anticoagulant therapy should be compliant with their medications to prevent recurrent thrombolic events; emphasize compliance.
• Avoid vitamin K–containing foods such as green leafy vegetables, including spinach, broccoli, and cauliflower.
• Varicose veins coexist commonly with cyanotic congenital heart disease, and these may predispose to thromboembolic phenomena. These patients should avoid passive standing, should avoid crossing their legs when sitting, and should not allow their legs to be dependent.
• Avoid Valsalva maneuvers 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.
• For excellent patient education resources, visit eMedicine's Circulatory Problems Center. Also, see eMedicine's patient education article Blood Clot in the Legs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The clinical presentation of PDE is nonspecific. Therefore, PDE is a diagnostic challenge that is prone to misdiagnosis, which may result in medicolegal action by the patient and family. PDE mimics other diseases, and suspicion should be high in order to avoid medicolegal implications.
• Outcome may be devastating with complications such as neurological 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.
• Adverse reactions from intravenous contrast agents may occur in studies such as venography, arteriography, angiography, and cardiac catheterization. Obtaining an informed consent with full explanation about the indications, implications, and complications of the procedure and the possibility of contrast-associated adverse reactions is important.
• Appropriate treatment can lead to morbidity and mortality. Thrombolytic treatment can lead to intracranial hemorrhage with extensive neurologic deficits. Transcatheter closure of PFO may lead to residual shunting due to malalignment of the occluder device; this can cause recurrent strokes.
• Surgical intervention, in the form of embolectomy and closure of PFO, in the presence of intracardiac embolus and PFO has a survival rate of 75% and death rate close to 25%. In view of all the complications of treatment, the benefits should be weighed against the risks. To avoid medicolegal pitfalls, patients and their families should be provided with a thorough explanation about the outcome of the intervention.

Special Concerns

• PDE is not common in pediatric age groups.
• PDE in pregnancy is rare but possible because of increased risk of DVT. Noninvasive modalities should be chosen over an invasive workup, and the treatment mainly is 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 interruption a better choice than warfarin for long-term anticoagulation when DVT and PE are present in PDE.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jun 8, 2006