PULMONARY EMBOLISMPULMONARY EMBOLISM

Edward Hamaty D.O., FACCP, FACOI

Epidemiology

• Third most common acute cardiovascular disease – After coronary ischemia and stroke – Rate is 98 (nonfatal) and 107 (fatal) events per 100,000

persons in USA – Over 300,000 hospitalizations and 50,000 deaths per

year

• Mortality increases with age and male sex • 40% (idiopathic / primary PE's) have increased

incidence of developing overt cancer (9.1%-11.5% will HAVE occult cancer at time of PE diagnosis)

• 10-20% of persons with PE have genetic thrombophilic disorders

• Patients with PE are at increased risk (>1.5X) of death within 6 months of diagnosis

Predisposing Factors

• History of DVT, Concurrent DVT >95% of patients with PE; PE occurs in >50% of cases with phlebographically confirmed DVT [31]    

• Obesity ~40% (of cases) - risk is 1.7-3.2X versus non-obesity (Primarily women with BMI ≥29 kg/m2)

• Cancer ~30% • Heart Failure ~35% • Surgery - perioperative and up to 30 days post

surgery, ~20% • Fracture ~20% • Smoking (> 25 cigarettes/day)• Shock • Air Travel - particularly >3100 miles (5000 km) [51]

Predisposing Factors- con’t.

• Intake of (high doses of) Estrogen        – Especially in smokers, mainly on birth control

pills (oral contraceptives, OCP) – Third generation OCP have ~2X increased

risk of thromboembolism versus 2nd generation

– Estrogen replacement therapy (ERT): increase risk ~1.2-2X in current users [6,8]

– Factor V Leiden patients on OCPs may have >30X increased risk of thromboembolism [30]

• Trauma • Pregnancy: peri- and post-partum • Tumor Microembolization

Predisposing Factors- con’t.• Hypercoagulable States       

– Factor V Leiden - Resistance to Activated Protein C (~12% of PE cases) [44]

– Factor II (Prothrombin) 20210A mutation - (~10% of PE cases) [44] It was discovered in 1996 that a specific change in the genetic code causes the body to produce an excess of the prothrombin protein.

– Protein C, S or Antithrombin III Deficiency – Acquired - antiphospholipid antibodies, paraneoplastic

syndromes – Low levels of tissue factor pathway inhibitor (TFPI)Elevated clotting factors and homocysteine likely contribute

• Hypertension - at least in women [5] • Thrombosis of axillary subclavian vein (Paget-Shroetter

syndrome) [55]

Clotting Cascade

F5L

20210A mutation ↑ F II

RISK FACTORS FOR VENOUS THROMBOEMBOLISM

THROMBOPHILIAS AND PE/DVT

THROMBOPHILIAS AND PE/DVT

High Risk for Fatal Outcome • Cancer

– ~15% of underlying cancer if >1 independent episode of PE

– Low yield for finding occult malignancy if second event is induced (for example, by surgery)

• Congestive Heart Failure (CHF) • Chronic underlying lung disease • Recurrent PE • Elevated troponin (T or I) levels in setting of PE

was associated with an increased risk of short-term mortality (OR 5.24, 95% CI 3.28-8.38) or death due to PE (OR 9.44, 95% CI 4.14-21.49) [32].

High Risk for Fatal Outcome • Pulmonary Hypertension (P-HTN) [55,64]

– Chronic recurrent PE with progression to P-HTN – Overall incidence of P-HTN ~4% within 2 years of

initial PE [64] – Persistent right ventricular (RV) dysfunction after PE

increases risk for recurrent DVT by 2.4X [31]• BNP: An elevated brain natriuretic peptide (BNP) or N-

terminal pro-brain natriuretic peptide (NT-proBNP) predicts RV dysfunction and mortality [15,16]. This was illustrated by two meta-analyses:

– A meta-analysis of 16 studies found that short-term mortality was increased 6-fold among patients with a BNP >100 pg/mL and 16-fold among patients with an NT-proBNP >600 ng/L [16].

– A meta-analysis of 13 studies (1132 patients) found that 30-day mortality was increased among patients with an elevated BNP or NT-proBNP (odds ratio 7.6, 95% CI 3.4-17) [17].

High Risk for Fatal Outcome • BNP and NT-proBNP may predict other adverse outcomes.

– In an observational study of 73 consecutive patients diagnosed with acute PE, serum BNP levels >90 pg/mL (drawn within four hours of presentation) were associated with cardiopulmonary resuscitation, mechanical ventilation, vasopressor therapy, thrombolysis, and embolectomy, as well as death.

– Serum BNP levels <50 pg/mL identified 95 percent of patients with a benign clinical course.

– Troponin T > 0.07 mcg/L plus NT-proBNP ≥ 600ng/L had higher 40 day mortality vs Trop T > 0.07 and NT-proBNP < 600 (33 vs 0 %)

• RV thrombus — Patients with PE and a right ventricular (RV) thrombus have a higher 14-day mortality (21 versus 11 percent) and three-month mortality (29 versus 16 percent) than patients without an RV thrombus.

• Overall, few patients have recurrent emboli, particularly after initiation of therapy

Pathogenesis    • Clot forms at distal site, usually in distal veins in

the leg or in pelvic veins • Clots usually initiated by hypercoagulable state,

risk factors above, usually combination • Clots migrate to pulmonary vasculature

– Most clots lodge in pulmonary arterioles or segmental arteries

– Lodging at pulmonary artery bifurcation leads to "saddle" embolism

• Lodged thrombi release vasoconstrictors        – Serotonin – Thrombin – Endothelin

• Others

Pathogenesis – con’t.• Release of these vasoconstrictors causes diffuse

pulmonary vascular constriction – P-HTN follows        – Severe, particularly acute, P-HTN can cause right heart

failure – In addition, can cause cardiac arrest (likely due to acute P-

HTN) [11,43] – Jugular venous distension on clinical exam has poor

sensitivity for severe P-HTN [55] • Alveolar Dead Space

– Vascular blockade (full or partial) leads to unperfused areas of lung

– These areas are called dead space (ventilated but not perfused)

– Alveolar dead space increases in PE in proportion to severity of vascular blockade

– Alveolar dead space can be estimated from difference of exhaled and arterial CO2 levels

Pathogenesis – con’t.

• Loss of gas exchange surface also occurs (reduced diffusion limit of carbon monoxide)

• Pulmonary Tumor Embolism [62] – Presentation similar to more common

thromboembolic PE – Incidence ~15% amongst patients with solid

tumors – Breast, stomach, lung, liver cancers most

often reported – Consider in any patient with cancer who

presents with acute dyspnea

Pathology

Cardiac Consequences of Acute PE

Symptoms [13] • Symptoms are non-specific, not very sensitive;

high suspicion must be maintained • Dyspnea 77% (A-a gradient) • Tachypnea 70% • Chest Pain 55% (usually pleuritic) • Tachycardia 43% • Cyanosis 18% • Hemoptysis 13% • Syncope 10% • Systemic embolism may occur in patients with L-

R shunts [1] • Pleuritic chest pain in absence of dyspnea is

common first presentation [10] • Sudden cardiac arrest with pulseless electrical

activity [43]

Symptoms – con’t.

• Cough 43%• Leg Swelling 33%• Leg Pain 30%• Palpitations 12%• Wheezing 10%• Angina-like pain 5%

Differential Diagnosis • Myocardial Infarction [13]        • Pneumonia        • Pulmonary Edema / Congestive Heart Failure

       • Asthma, COPD Exacerbation        • Intrathoracic Cancer • Pericardial Tamponade        • Pneumothorax • Rib Fracture • Musculoskeletal Pain, Costochondritis • Sarcoma of the pulmonary artery (rare) [41] • Dissecting Thoracic Aneurysm        • Primary Pulmonary Hypertension       • Anxiety / Panic Attack

PE Prediction Rules "Evaluation for Pulmonary Embolism"

• Suspicion should be high if ANY risk factors or symptoms/signs are present

– >70% of patients who die of PE are not suspected of having it

– Only ~35% of patients suspected of having PE actually have it

– Pre-test probability is very important for making clinical (diagnostic) judgements

– PE testing is less reliable in older persons than in younger persons [42]

– Age is a major risk factor, particularly with underlying predisposing conditions

Clinical Probability Calculation [3,10]

– Risk factors are assigned points – Modified Well’s Score– Low (<2.0), Intermediate (2.0-6.0) High (>6.0) clinical

probability assigned – Clinical signs and symptoms of DVT: 3.0 points – Alternative diagnosis deemed less likely than PE: 3.0

points – Heart rate >100 beats per minute: 1.5 points – Immobilization or surgery in previous 4 weeks: 1.5

points – Previous DVT or PE: 1.5 points – Hemoptysis: 1.0 points – Cancer: 1.0 points – Clinical probabilities are used to determine evaluation – Clinical suspicion in experienced physicians likely as

good as quantitative evaluation [27] • More complex clinical prediction rules have been

created with similar accuracy as above

Wells Clinical Prediction Rule for PE

Evaluation Scheme Based on Clinical Probability [10,63]

– Low clinical probability: high sensitivity D-dimer (level <500µg/L) to rule out PE

– Lower extremity venous ultrasound (US) to rule in DVT – Helical CT angiography or V/Q scanning can also be

used to rule out PE in low probability – Intermediate probability: CT angiography or V/Q

scanning – High clinical probability: CT angiography or V/Q

scanning – Helical CT scan may substitute for V/Q scan when

combined with lower extremity US [1] – Helical CT scan can be used safely as primary

diagnostic test to rule out PE [57,58] – Negative CT angiography results effectively rule out

PE as well as standard angiography [] – Additional testing is done following results of initial test

Evaluation Scheme Based on Clinical Probability [10,63]

V/Q Scans• VQ scan results correlated reasonably well with positive

pulmonary angiograms in PIOPED [15] – Goal is to limit pulmonary angiography to a minimum number of

patients – Helical CT angiography is generally preferred over V/Q scanning – Computerized tomographic (CT) pulmonary angiography is as

effective as standard pulmonary angiography and safer for ruling out PE [9]

– Percentages are % of patients with positive pulmonary angiograms in PIOPED Study [15]:

• V/Q Scan High PTP Intermediate Low• High probability 95% 86% 56%• Intermediate 66% 28% 15%• Low probability 40% 15% 4%• Quantitative prediction tools recommended for initial pre-

test probability prediction [27]

V/Q Scan AND Clinical Probability

Specific Evaluation [32,42,63]

• Routine Laboratory Tests in Suspected PE

– Electrolytes, complete blood count, coagulation parameters (PT, aPTT)

– ECG (standard) and ECG with right sided leads on all patients

– All patients should have an Arterial Blood Gas (ABG, preferably on room air)

– A PaO2 between 85 and 105 mmHg exists in approximately 18 percent of patients with PE

– Normal A-a gradient found in <6% of patients with PE (see below)

– High Sensitivity D-Dimer Test – Lower extremity venous US with doppler

measurements

ECG Changes – Most common ECG is

normal sinus rhythm: 23% of submassive, 6% of massive PE

– Sinus Tachycardia extremely common

– Right Axis Deviation; S in I, Q in III, inverted T in III "classic changes" but uncommon

– If classic changes are present, anticoagulation should be started, pursue evaluation

– Right sided leads should be evaluated       

High Sensitivity D-Dimer [17,33]

– High negative predictive value for PE (based on pulmonary angiography)

– For D-dimer <500ng/mL, negative predictive value (NPV) 91-99% [36] – For D-dimer >500ng/mL, sens=93%, spec=25%, and positive predictive

value (PPV) = 30% – Test is also useful for DVT rule out (<500ng/mL): NPV 92% – For indeterminant V/Q scans, combination of D-Dimer and

ultrasonography gave a definitive diagnosis in 62% of patients (others underwent angiography) [16]

– SimpliRED bedside D-dimer test + alveolar dead space [ADS] calculation can be used in place of V/Q scans to rule out PE [36,46] Most patients with a normal ADF and a negative D-dimer do not have PE (98 percent)

– Use of D-dimer test alone to rule out PE may not appropriate [39,40,46] – D-Dimer testing has reduced specificity in older persons (~10%) versus

<40 years (67%) [42] – Patients with normal D-Dimer combined with low pretest clinical

probability of PE could be safely discharged without further evaluation (NPV >99.5%) [33,49,50]

– D-Dimer testing should be included in evaluation of PE in nearly all ambulatory patients

– D-Dimer less helpful for hospital inpatients (elevations common and unrelated to PE)

Hi Sensitivity D-Dimer– High negative predictive value for PE

(based on pulmonary angiography) – For D-dimer <500ng/mL, negative

predictive value (NPV) 91-99%– For D-dimer >500ng/mL, sens=93%,

spec=25%, and positive predictive value (PPV) = 30%

– PPV and NPV are affected by PPV and NPV are affected by prevalence.prevalence.

– Test is also useful for DVT rule out (<500ng/mL): NPV 92%

– If pretest probability is intermediate (27.8) you are supposed to image, but if you order a D-Dimer what do the results mean?

Prevalence of 27.8% (Well’s Intermediate), Sensitivity of 93%, Specificity of 25%

28

72

26

54

100

80 people test positive……….

of whom 26 have the disease

So, chance of disease is 26/80 about 32.5%

(PPV quoted at

30%)

Disease +ve

Disease -ve

Testing +ve

Sensitivity = 93%

False positive rate = 75% (1-Sp)

Incidence of PE in the General Population

• 650,000 to 900,000/year• Current US Population = 307,085,301

Incidence Ranges :– From 650,000/307,085,301 = 0.0021 or

2/1000– To 900,000/307,085,301 = 0.00293 or

3/1000– Admittedly this includes newborns,

children, etc. but is being used for illustrative purposes.

Prevalence of 0.003%, Sensitivity of 93%, Specificity of 25%

3

997

3

748

1000

751 people test positive……….

of whom 3 have the disease

So, chance of disease is with a + test is 3/751 or about 0.4%

(The lowerlower the prevalence, the moremore false positives)

Disease +ve

Disease -ve

Testing +ve

Sensitivity = 93%

False positive rate = 75% (1-Sp)

Sensitivity and specificity don’t vary with prevalence

• Test performance can vary in different settings/ patient groups, etc.

• Occasionally attributed to differences in disease prevalence, but more likely is due to differences in diseased and non-diseased spectrums

D-Dimer

D-Dimer

• False Positive D-Dimer– Pregnancy– Trauma– Postoperative Recovery– Inflammation– Cancer– Rheumatoid Factor– Older Age

• False Negative D-Dimer– Heparin

D-Dimer

CXR

CXR Atelectasis Hampton’s Hump

Prominent PA

Westermark’s Sign

Ventilation-Perfusion (V/Q) Scans [15]       

– High probability scans identify only ~50% of patients with PE overall

– Abnormal (high + intermediate + low prob) scans detect 98% of PE's, but low specificity

– About 60% of V/Q scans will be indeterminant (intermediate + low probability)

– Of intermediate probability scans, ~33% occur with angiographically proven PE

– Test results not affected by presence of pre-existing cardiac or pulmonary disease

– Conclude: normal test rules out PE in ~98% of cases – Note that low probability test still has ~15-25% chance of PE – However, there were no deaths due to PE within 6 months in

a study of 536 patients with low probability scans [35] – Further evaluation is clearly required for intermediate

probability scans – For low probability scan with normal D-dimer level, no

additional workup needed – Consider helical CT in patients with non-diagnostic V/Q scan

[45] – NPV of helical CT with nondiagnostic V/Q is 96% [45]

Ventilation-Perfusion (V/Q) Scans

V/Q with Large Defect

V/Q with Multiple Defects

V/Q with Subsegmental Defects

Lower Extremity Doppler US [18,19,34]

– To evaluate for DVT as possible cause of PE or to help rule in PE

– Up to 40% of patients with DVT without PE symptoms will HAVE a PE by angiography

– Serial US should be probably be performed in patients with abnormal (or non-diagnostic) V/Q scans and positive D-Dimers [34]

– These US should be carried out on days 1, 3, 7, and 14 [32]

– A positive US on any of these days with abnormal V/Q rules IN a PE [32]

• Negative serial US scans reduce likelihood of PE to <2% [20]

Venous UltrasoundNormal Compression US DVT Location of Vein Marked

DVT Vein Resisting Compression Normal Color Doppler

Venous Ultrasound

A subtotal occlusive thrombus in the right popliteal vein is shown in this colour Doppler image.

Right lower extremity (A) transverse and (B) saggital images from color Doppler ultrasound demonstrates blood flow in the femoral artery but not in the common femoral vein (arrows). This is an indirect finding that suggests common femoral DVT.

Helical (Spiral) Computed Tomography (CT) [22,37,48]       

– Helical CT scanning produces volumetric two-dimensional image of lung

– This is accomplished by giving IV contrast agent and rotating detector around the patient

– Total acquisition time is <30 seconds – PE appears as a filling defect that may be

central, eccentric or mural – The embolism may completely or partially

occlude the vessel – Test is very quick, requires IV contrast and

careful interpretation and is costly

Helical (Spiral) Computed Tomography (CT)

– Reported sensitivity 53-100% (83% in PIOPED II) , specificity 81-100%. (96% in PIOPED II) N Engl J Med. 2006 Jun 1;354(22):2317-27.

– PE rate with negative helical CT and lower extremity ultrasound in patients with moderate or low clinical probability PE is ~2%, high clinical probability PE ~5% [57]

– Thus, anticoagulation can be safely withheld in moderate to low clinical probability patients with negative helical CT and lower extremity ultrasound [57]

– Combination of helical CT with lower-extremity ultrasonography and V/Q scan may avoid invasive angiography [48]

– Helical CT alone can be used safely to rule out PE [58] – Helical CT appears to increase the diagnosis of PE

and reduce angiography [22]

Helical (Spiral) Computed Tomography (CT)

CT – con’t.

Infarct

CT Pre and Post Lytic Therapy

A-a Gradient in Evaluation for PE [14]

– Normal A-a gradient may be seen in PE in ~6% of patients with PE [1]

– An arterial blood gas should be done to determine the level of respiratory dysfunction. A PaO2 between 85 and 105 mmHg exists in approximately 18 percent of patients with PE.

– A-a gradient depends on age and body position        – In supine position, Normal A-a Gradient ~ 103.5-

0.42xAge – ~2% of patients with normal A-a gradient, no history of

DVT/PE, had abnormal V/Q scan – Normal A-a gradient in patients with low pretest

probability makes PE very unlikely – Pulse oximetry >95% on room air at diagnosis

associated with low risk of serious morbidity [61] – A-a gradient is not currently a recommended part of

decision making in PE

Echocardiography [53]

– Transthoracic echocardiography is not sensitive as screening test to rule out PE [47]

– However, echocardiography is a very sensitive indicator of massive or unstable PE

– Echocardiography should be done on any patient with suspected massive or unstable PE

– Also critical for selecting patients for thrombolysis or other aggressive therapy [4]

– Right ventricular (RV) function is most predictive of outcomes – About 40% of patients with PE and normal blood pressure (BP)

have abnormalities of the RV – Unstable patients include those with RV hypokinesis, dilation,

abnormal septal motion, patent foramen ovale, free floating right-heart thrombus

– Large PEs predicted by >30% loss of blood flow to either lung (on V/Q Scanning)

– Pulmonary artery pressures can be estimated (physical exam has poor sensitivity) [56]

– May be used for chronic monitoring of P-HTN as well [52]

Echocardiography

EchocardiographyRV greater than LV with septal shift

Echocardiography

Clot in RA Clot in RV

Echocardiography

Echocardiography

Echocardiography

Echocardiography

Contrast Pulmonary Angiography

– This has been the gold standard for diagnosis but it is highly invasive

– The pulmonary catheter may also be used therapeutically (angioplasty)

– Angiography can be avoided in most patients by using other tests above

– Positive result is a filling defect or sharp cutoff in a pulmonary artery branch

– A negative angiogram with magnification excludes clinically significant PE

– Increased sensitivity is obtained with subselective dye injection

– May be morbid with worsening shortness of breath, artery perforation, others

– Spiral CT scanning can be used to detect proximal PEs instead of angiography [1]

– CT pulmonary angiography is safer than standard invasive angiography and can be used to effectively rule out PE [9]

Contrast Pulmonary Angiography

Contrast Pulmonary Angiography

Contrast Pulmonary AngiographySelective Angiography with Clot

Contrast Pulmonary Angiography-Normal

Contrast Pulmonary Angiography-Abnormal

Magnetic Resonance Angiography (MRA) [21]

– Techniques for use of MRA for diagnosing PE are evolving rapidly

– Estimated sensitivity ~80% (~100% for larger emboli), specificity 95%

– Non-invasive with little morbidity – Dynamic gadolinium enhancement is

used, allowing high quality images – Strongly consider prior to standard

invasive pulmonary angiography

Magnetic Resonance Angiography (MRA)

MRAAfterresolution

Consider Underlying Causes       

– Inherited Clotting Abnormalities: deficiency in Protein S, C, or ATIII

– Underlying malignancy - may alter Factor Va activity

– Collagen Vascular Disease: anti-phospholipid syndrome, systemic lupus

Treatment Overview       

• Anti-Coagulation is Mainstay of Therapy [7,29]       

– Standard or low molecular weight (LMW) heparin equal in efficacy, safety

– Standard heparin bolus 5000U - 10,000U (higher for large PE) then 1000-1500U / hour

– LMW heparin is usually given as fixed or weight-adjusted qd or bid dose

– Unlike standard heparin, LMW heparin does not require monitoring or adjustment in partial thromboplastin time (PTT) [29]

– Heparin is usually used as a bridge to warfarin therapy

Anti-Coagulation - Heparin

Anti-Coagulation - Warfarin

Oral Direct Thrombin Inhibitors

• Ximelagatran, an oral direct thrombin inhibitor has shown promising efficacy, is well tolerated, and at least as effective as warfarin, but it does not require coagulation monitoring or dose adjustment .

Thrombolytic Therapy

– Tissue plasminogen activator (TPA) or streptokinase are usually used

– Usually given to patients with echocardiographic evidence of right heart strain / failure

– Alteplase beneficial when added to heparin in stable PE patients with right hear strain [54]

Embolectomy

– Surgical embolectomy (thrombectomy) only in very selective cases

– Perioperative morality is 25-50% – Massive pulmonary embolism where

thrombolysis contraindicated – Chronic thromboembolic pulmonary

hypertension

Treatment Algorithm for Acute PE

IVC Filter Placement [60]

– Usually, "Bird's Nest Filter" is placed in IVC

– Generally reserved for patients with recurrent PE on anti-coagulation

– May also be used for patients in whom anti-coagulation is contraindicated

– Can be used as adjunct in massive PE where thrombolysis is not an option

– Generally these are an accepted therapy and fairly safe to implant

IVC Filter Placement

• Indications — Insertion of an inferior vena cava (IVC) filter is indicated for acute PE in the following settings [31]:

• Absolute contraindication to anticoagulation (eg, active bleeding)

• Recurrent PE despite adequate anticoagulant therapy • Complication of anticoagulation (eg, severe bleeding) • Hemodynamic or respiratory compromise that is severe

enough that another PE may be lethal • Patients who have undergone embolectomy (surgical or

catheter) frequently undergo IVC filter insertion. • In addition, IVC filters are being used for PE prophylaxis in

select groups of patients. While the evidence base for these indications is less robust, it appears reasonable to individualize such cases and consider this approach.

IVC Filter Placement• Outcome — IVC filters decrease recurrent PE [34,35]. However, a reduction in

mortality has not been conclusively demonstrated. One study suggested that IVC filters may decrease mortality in patients with persistent hypotension due to PE (ie, massive PE), but this is uncertain because the patients who received IVC filters were younger and the effect of age was not considered [32].

• In one trial, 400 patients with proximal deep venous thrombosis (DVT) were randomly assigned to receive anticoagulation alone or anticoagulation plus an IVC filter [34]. The trial found:

• Fewer patients in the IVC filter group suffered PE within twelve days (1 versus 5 percent).

• Two years later, there was no difference in survival or symptomatic PE. However, recurrent DVT was more common among patients who received an IVC filter (21 versus 12 percent).

• Eight years later, there were fewer symptomatic PE in the IVC filter group (6 versus 15 percent). However, recurrent DVT was more common among patients who received an IVC filter (36 versus 27 percent) [35].

• This trial suggests that the benefit of decreased recurrent PE must be weighed against the consequence of increased recurrent DVT when deciding whether an IVC filter should be placed in a patient with acute PE.

IVC Filter Placement

• Complications — Complications of IVC filters are rare but include [34,36]:

• Complications related to the insertion process (eg, bleeding, venous thrombosis at the insertion site).

• Filter misplacement. • Filter migration. • Filter erosion and perforation of the IVC wall. • IVC obstruction due to filter thrombosis.

Danaparoid [23]

– A heparinoid obtained from pig intestinal mucosa after removal of heparin

– Combination of heparan sulfate (84%), dermatan sulfate (12%), chondroitin sulfate (4%)

– Major activity is selective inhibition of Factor Xa through antithrombin III

– High dose (2000U sc bid) more effective than heparin iv in DVT and PE

Chronic Therapy with Warfarin or SC standard or LMW Heparin  

– Usually maintained for 3-6 months after PE to prevent recurrence

– 6 month therapy has nearly half of the recurrences as 6 week therapy [24]

– Prolonged anticoagulation reduced risk of recurrence 80% versus 3 months [59]

– INR of 2-2.85 is recommended in most cases – Patients with underlying coagulopathy may require

longer term or lifelong therapy – Overall risk of recurrence is ~2.5% during the 6-month

period of therapy – Serious bleeding complications occurred in 3.3% of

patients • Chronic prolonged therapy is very effective in

eliminating risk of recurrent fatal PE [12,59]

Anti-Coagulation - Warfarin

Chronic Thromboembolic Pulmonary Hypertension [52]

– Pulmonary thromboendarterectomy for symptomatic disease

– Contraindication to surgery is severe underlying chronic lung disease

• If surgery deferred, close monitoring for progression is required      

Thrombolysis [4,25,54]        • Indications

– Hemodynamic instability – RV Dysfunction (by echocardiogram) - RV

Dilatation, abnormal septal motion [54] – Anatomically large PE - multiple segments on

V/Q Scan or Angiogram – Extensive DVT - controversial use (probably

decreases post-thrombotic syndrome) • Absolute Contraindications to

Thrombolysis        – Active or recent internal bleeding – History Hemorrhagic Stroke – Intracranial Neoplasm – Recent cranial surgery or head trauma

Thrombolysis• Relative Contraindications

– Major surgery (within 10 days) – Cardiopulmonary Resuscitation (CPR) – Invasive procedure with 10 days inaccessible to external compression – Pregnancy – Coagulopathy – Severe Hypertension, uncontrolled – CVA (non-hemorrhagic) – Pulmonary Angiography + TPA has14% risk of major bleed vs. 4% in TPA

alone [26] • Dosing

– No dosage adjustments needed – Initial: SK 250,000U over 30 minutes; UK 2,000U/pound over 10 minutes – Then: SK 100,000U per hour x 24 hours; UK 2,000U/pound/hour x 12-24

hours – TPA given 100mg over 2 hours or 0.6mg/kg over 3 minutes [54] – After administering thrombolytics, start heparin (dose by following PTT) – Coumadin may be added on 2nd day of heparin, but overlap should continue

>4 days – Pregnant patients are given full dose sc heparin instead of coumadin

Thrombolysis• Benefits of Thrombolysis [4,25]

– Emboli clear faster with thrombolytics than with anticoagulation [18]

– Reduce pulmonary artery pressure and improve echocardiogram at 2 and 24 hours

– Reduce risk of combined endpoint of death or decompensation [54]

– No differences in overall survival in most studies – Improves longer term RV function in some studies with

thrombolytics – Thrombolytics increase risk of severe hemorrhage

including intracranial bleeding – Rate of major hemorrhage with thrombolysis is low,

however (<10%) [31] – In patients with RV dysfunction but normal systemic

BP, major bleeding in 0% [54]

Thrombolysis

Primary Prevention of PE [1]       

• Heparins        – Low-dose Heparin 5000U sc bid-tid was the standard

agent – LMW heparin appears to be more effective for

prophylaxis than standard heparin – Variety of low dose heparins and heparinoids have

been used – Enoxaparin or Dalteparin (sc qd)

• Low dose (INR ~1.5X control) warfarin may also be effective       

• Aspirin 160mg po qd may be added to other agents and reduces DVT and PE incidence by about 30% after major orthopedic surgery [38]

• Compression stockings should be used in ALL patients unless contraindicated

Primary Prevention of PE

• Inferior Vena Cava (IVC) Filters [28] – Consider use for prophylaxis in patients at

high risk for PE – Majority of these patients have large,

proximal DVTs – IVC Filters appear to reduce early PEs (at12

days) by 80% – However, in 2 year followup, IVC filters

increased risk of PE by nearly 2-fold

• Leg elevation (following surgery, stroke) may also prevent DVT's

Primary Prevention of PE

Primary Prevention of PE

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