PULMONARY

THROMBOEMBOL
ISM

August 2012
The pulmonary circulation is characterized by an inflow pressure or
pulmonary artery pressure (Ppa), an outflow pressure or left atrial
pressure (Pla), and a pulmonary blood flow (Q) approximately equal
to systemic cardiac output. Pulmonary vascular pressures and flows
are pulsatile.
PVR=(mPpa-Pla)/Q
Measurements of pulmonary vascular pressures and cardiac
output are usually performed during a catheterization of the
right heart with a fluid-filled balloon-tipped thermodilution catheter
Compared
with nonpregnant women, the risk of venous thrombotic events
is increased fivefold during pregnancy and 60-fold in the first
3 months after delivery.13,14 The increase may be a result of decreased
mobility, pregnancy-related hypercoagulable state (increases in factors
II, VII, VIII, X, acquired activated protein C resistance, and
decreased free protein S level), and venous obstruction from uterine
compression.
DVT & Pulmonary Thromboembolism: Introduction

Epidemiology

 VTE, which encompasses DVT and PE, is one of the 3 major

cardiovascular causes of death, along with MI & stroke.

 VTE can cause death from PE or, among survivors, chronic

thromboembolic pulmonary HTN & postphlebitic syndrome.

 B/n 100,000 and 300,000 VTE-related deaths occur annually in the

US.

 ~3/4th of symptomatic VTE events occur in the community, and the

remainder are hospital acquired.
DVT & Pulmonary Thromboembolism:
Introduction…

 The long-term effects of nonfatal VTE lower the quality of life.

 Chronic thromboembolic pulmonary HTN is often disabling and causes

breathlessness.

 Postphlebitic syndrome
 Also known as postthrombotic syndrome or chronic venous insufficiency
 Is a late effect of DVT & eventually occurs in >1/2 of DVT patients.

 Causes the venous valves of the leg to become incompetent and exude
interstitial fluid.
 Patients complain of chronic ankle or calf swelling and leg aching, especially
after prolonged standing.
 In its most severe form, postphlebitic syndrome causes skin ulceration,
especially in the medial malleolus of the leg.
 There is no effective medical therapy for this condition.
Prothrombotic States

 Thrombophilia contributes to the risk of venous thrombosis.

 The 2 most common autosomal dominant genetic mutations are:

 Factor V Leiden, which causes resistance to activated protein C (which
inactivates clotting factors V and VIII), and
 The prothrombin gene mutation, which increases the plasma prothrombin
concentration.

 Antithrombin, protein C, and protein S are naturally occurring

coagulation inhibitors.

 Deficiencies of these inhibitors are associated with VTE but are rare.
Antithrombin Deficiency

Antithrombin is a plasma protease inhibitor that irreversibly binds and

neutralizes thrombin and factors Xa, IXa, and XIa, resulting in reversal of
coagulation cascade. This reaction is accelerated by heparin. Therefore,
antithrombin deficiency increases risk of thrombosis. Antithrombin
deficiency is
relatively rare but is considered one of the more severe thrombophilias
Prothrombin G20210A Mutation
The prothrombin G20210A mutation is a substitution mutation that results in
increased levels of plasma prothrombin, leading to increased generation of
thrombin. Assays of prothrombin time or prothrombin antigen are neither
specific nor sensitive enough for diagnosis; therefore, diagnosis is made by
genotype analysis.
Activated Protein C Resistance/Factor V Leiden

This is the most common hereditary thrombophilia in the Caucasian

population
. More than 90% of patients with activated protein C resistance have the
G1691A mutation in the factor V gene (factor V Leiden), which decreases
the rate of
proteolytic cleavage by activated protein C. Activated protein C resistance
test
should be used for screening before obtaining factor V Leiden mutation
genotype.; in a positive test, the addition of activated protein C fails to
cleave factor V, resulting in prolongation of PTT. Diagnosis is often
confirmed by detection of the factor V Leiden mutation by a DNA-based
assay. The risk for VTE in heterozygous patients who use oral
contraceptives is increased 35-fold.
Type I antithrombin deficiency is characterized by both decreased levels and
decreased activity, whereas type II is characterized by decreased protease activity,
with defects in either the active center or the heparin-binding site. Thus, resistance
to the anticoagulant effects of heparin is seen in some patients. There is no difference
in clinical severity between type I and type II. Antithrombin activity assays and
antigen levels are used to make the diagnosis.
Acute thrombosis, heparin, liver disease, DIC, nephrotic syndrome, and
preeclampsia can all decrease antithrombin levels; therefore, diagnosis should not
be made on the basis of levels obtained under these conditions.
Prospective studies indicate that the incidence of VTE in these patients is 4%
per year. Nearly 70% of patients present with the first thrombotic event before age
35 years.
Protein C and S Deficiency

Proteins C and S aHomozygous protein C deficiency can cause neonatal purpura fulminans.
Patients
with either protein C or protein S deficiency can present with warfarin skin necrosis
at the initiation of anticoagulation due to a transient hypercoagulable state.
Protein C deficiency is diagnosed by an assay to detect activity followed by
immunoassays to differentiate type I (reduced antigen and activity) and type II
(reduced activity) defects. Protein S binds to a plasma protein so that free protein S
antigen and activity are used to screen for protein S deficiency and differentiate
among type I (decreased antigen and activity), type II (decreased activity), and type
III (low free protein S). DNA-based assays are not practical in both protein C and
protein S deficiency, given that >150 mutations in the protein C gene have been
described. Protein C and S levels are affected by liver disease, anticoagulation with
warfarin, nephrotic syndrome, DIC, vitamin K deficiency, oral contraceptives,
pregnancy, and hormone replacement therapy.re vitamin K-dependent endogenous anticoagulants
Elevated Factor VIII Levels

Increased factor VIII levels have been associated with an increased risk of
thrombosis (relative risk = 4.8). Elevated levels are found with increased
age,
obesity, pregnancy, surgery, inflammation, liver disease, hyperthyroidism,
and
diabetes. No gene alteration has been found, although familial clustering
of
increased factor VIII levels is noted. It is unclear how increased factor
VIII levels
lead to increased thrombotic risk and how elevated factor VIII levels may
affect
treatment of thromboembolism.
Consideration of a hypercoagulable workup is usually
recommended in patients with
Recurrent VTE, especially unprovoked thrombosis
Thrombosis at a young age (< 50 years)
Thrombosis at unusual sites (cerebral sinus, mesenteric vein, portal
vein, hepatic vein)
Recurrent second or third trimester fetal loss, placental abruption, or
severe preeclampsia
The optimal time for testing patients for hereditary defects is not
well defined, but performing the thrombophilic evaluation at the time of
thrombosis is not advised because it often leads to misleading results
Prothrombotic States…

 Antiphospholipid antibody syndrome(APS) is the most common

acquired cause of thrombophilia
 APS is associated with venous or arterial thrombosis.

 Other common predisposing factors include :

 Cancer,
 Systemic arterial HTN ,

 COPD ,

 Long-haul air travel, Air pollution,

 Obesity,

 Cigarette smoking,

 Eating large amounts of red meat,

 Oral contraceptives, Pregnancy, Postmenopausal hormone replacement,

 Surgery, and trauma.

 Pathophysiology - VTE

Embolization

 When venous thrombi are dislodged from their site of formation, they
embolize to either:
 The pulmonary arterial circulation or,
 Paradoxically, to the arterial circulation through a patent foramen ovale or
atrial septal defect.

 ~1/2 of patients with pelvic vein thrombosis or proximal leg DVT develop
PE, which is often asymptomatic.

 Isolated calf vein thrombi pose a much lower risk of PE but are the most
common source of paradoxical embolism.

 Upper extremity venous thrombi rarely embolize and cause PE.

 Most PE arise from thrombi in the deep venous system of the lower extremities. However,
they may also originate in the right heart or the pelvic, renal, or upper extremity veins.
 Iliofemoral veins are the source of most clinically recognized PE [ 33-36 ]. It is estimated
that 50 to 80 percent of iliac, femoral, and popliteal vein thrombi (proximal vein thrombi)
originate below the popliteal vein (calf vein thrombi) and propagate proximally. The
remainder arise within the proximal veins. Fortunately, most calf vein thrombi resolve
spontaneously and only 20 to 30 percent extend into the proximal veins if untreated. Most
lower extremity thrombi develop at sites of decreased flow, such as valve cusps or
bifurcations
 After traveling to the lung, large thrombi may lodge at the bifurcation of the main
pulmonary artery or the lobar branches and cause hemodynamic compromise. Smaller
thrombi continue traveling distally and are more likely to produce pleuritic chest pain,
presumably by initiating an inflammatory response adjacent to the parietal pleura. Only
about 10 percent of emboli cause pulmonary infarction, usually in patients with preexisting
cardiopulmonary disease. Most pulmonary emboli are multiple, with the lower lobes being
involved in the majority of cas
 Hypotension is due to diminished cardiac output
(CO), which results from increased pulmonary
vascular resistance (PVR) impeding right
ventricular outflow and reducing left ventricular
preload. PVR is increased from physical
obstruction of the vascular bed with thrombus and
vasoconstriction, the latter due to the effects of
inflammatory mediators and hypoxia.
In the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED
II), the following frequencies of symptoms and signs were noted among patients
with PE who did not have preexisting cardiopulmonary disease

>The most common symptoms were dyspnea at rest or with exertion (73 percent),
pleuritic pain (44 percent), cough (34 percent), >2-pillow orthopnea (28 percent), calf or
thigh pain (44 percent), calf or thigh swelling (41 percent), and wheezing (21 percent). The
onset of dyspnea was usually within seconds (46 percent) or minutes (26 percent).
 The most common signs were tachypnea (54 percent), tachycardia (24 percent), rales (18

percent), decreased breath sounds (17 percent), an accentuated pulmonic component of

the second heart sound (15 percent), and jugular venous distension (14 percent) .
 Circulatory collapse was uncommon (8 percent) . Among such patients, dyspnea was

present in 82 percent and either dyspnea or tachypnea was present in 91 percent.

Massive PE may be accompanied by acute right ventricular failure, manifested by
increased jugular venous pressure, a right-sided S3, and a parasternal lift.
 Symptoms or signs of lower extremity deep venous thrombosis (DVT) were common

(47 percent) . They included edema, erythema, tenderness, or a palpable cord in the calf
or thigh
Physiology : PE

 The most common gas exchange abnormalities are

 Hypoxemia (decreased arterial PO2) and
 An increased alveolar-arterial O2 tension gradient

 Other pathophysiologic abnormalities include the following:

 Increased pulmonary vascular resistance
 Impaired gas exchange

 Alveolar hyperventilation due to reflex stimulation of irritant receptors.

 Increased airway resistance due to constriction of airways distal to the

bronchi.
 Decreased pulmonary compliance due to lung edema, lung
hemorrhage, or loss of surfactant.
Right-Ventricular Dysfunction : In PE

 Progressive right heart failure is the usual cause of death from PE.

 Increased pulmonary vascular resistance RV wall tension rises

further RV dilation and dysfunction.

 RV contraction continues even after the LV starts relaxing at end-systole.

 The interventricular septum bulges into and compresses an intrinsically

normal LV.

 Diastolic LV impairment develops, attributable to septal displacement, &

results in:
 Reduced LV distensibility and
 Impaired LV filling during diastole.
Right-Ventricular Dysfunction : In PE…

 Increased RV wall tension :

 Compresses the right coronary artery,

 Diminishes subendocardial perfusion,

 Limits myocardial oxygen supply, and

 May precipitate myocardial ischemia and RV infarction.

 Underfilling of the LV may lead to a fall in LV CO and systemic arterial

pressure, thereby provoking myocardial ischemia due to compromised
coronary artery perfusion.

 Eventually, circulatory collapse and death may ensue.

 Diagnosis : VTE

Clinical Evaluation

 VTE mimics other illnesses, and PE is known as "the Great Masquerader,"

making diagnosis difficult.

 In DVT the most common history is a cramp in the lower calf

 The most common history in PE is unexplained breathlessness.

 In evaluating patients with possible VTE, the initial task is to decide on the
clinical likelihood of the disorder.

 Low likelihood of DVT or a low-to-moderate likelihood of PE initial

diagnostic evaluation with d-dimer testing alone w/t obligatory imaging tests.

 If the d-dimer is abnormally elevated, imaging tests are the next step.
A revised Geneva score requiring eight
clinical variables without gas exchange or radiographic information
was validated and published.Other clinical decision rules include
the PISA rule, the PERC (pulmonary embolism rule-out criteria)
rule, and the Charlotte rule. Although such scoring systems
have not proved to be more accurate than clinical assessment,
 Clinical Decision Rules - DVT

Low Clinical Likelihood of DVT if Point Score <=0 ; Moderate if Score Is 1

to 2; High if Score Is >=3
Clinical Variable Score
Active cancer 1
Paralysis, paresis, or recent cast 1
Bedridden for >3 days; major surgery <12 weeks 1
Tenderness along distribution of deep veins 1
Entire leg swelling 1
Unilateral calf swelling >3 cm 1
Pitting edema 1
Collateral superficial nonvaricose veins 1
Alternative diagnosis at least as likely as DVT –2
 Clinical Decision Rules for PE

High Clinical Likelihood of PE if Point Score Exceeds 4

Clinical Variable Score

Signs and symptoms of DVT 3.0

Alternative diagnosis less likely than PE 3.0

Heart rate >100/min 1.5

Immobilization >3 days; surgery within 4 weeks 1.5

Prior PE or DVT 1.5

Hemoptysis 1.0

Cancer 1.0
Clinical Syndromes & dDx - VTE

 Sudden, severe calf discomfort suggests a ruptured Baker's cyst.

 Fever and chills usually herald cellulitis rather than DVT, though
DVT may be present concomitantly.

 P/E may consist only of mild palpation discomfort in the lower calf.

 In massive DVT , the patient presents with marked thigh swelling

and tenderness during palpation of the common femoral vein.

 In extreme cases, patients are unable to walk or may require a cane,

crutches, or a walker.
The Revised Geneva Clinical
Prediction Score
Differential Diagnosis – VTE…

DVT
 Ruptured Baker's cyst
 Cellulitis
 Postphlebitic syndrome/venous insufficiency

PE
 Pneumonia, asthma, COPD
 Congestive heart failure
 Pericarditis
 Pleurisy: costochondritis, musculoskeletal discomfort
 Rib fracture, pneumothorax
 Acute coronary syndrome
 Anxiety
 Clinical syndromes – VTE…

 Upper extremity venous thrombosis may present with asymmetry in

the supraclavicular fossa or in the circumference of the upper arms.
 A prominent superficial venous pattern may be evident on the anterior
chest wall.

 Patients with massive PE present with:

 Systemic arterial hypotension &
 Usually have anatomically widespread thromboembolism.

 Those with moderate to large PE have:

 RV hypokinesis on echocardiography but
 Normal systemic arterial pressure.

 Patients with small to moderate PE have both:

 Normal right heart function and
 Normal systemic arterial pressure.
 They have an excellent prognosis with adequate anticoagulation.
 PE can be classified as acute or chronic. Patients with acute PE typically develop
symptoms and signs immediately after obstruction of pulmonary vessels. In
contrast, patients with chronic PE tend to develop slowly progressive dyspnea
over a period of years due to pulmonary hypertension.
 Acute PE can be further classified as massive or submassive:
 Massive PE causes hypotension, defined as a systolic blood pressure <90 mmHg
or a drop in systolic blood pressure of ≥40 mmHg from baseline for a period >15
minutes. It should be suspected anytime there is hypotension accompanied by an
elevated central venous pressure (or neck vein distension), which is not otherwise
explained by acute myocardial infarction, tension pneumothorax, pericardial
tamponade, or a new arrhythmia [ 1,2 ]. It is a catastrophic entity that frequently
results in acute right ventricular failure and death. When death occurs, it is often
within one to two hours of the event, although patients remain at risk for 24 to 72
hours [ 3,4 ]. The PE is frequently undiscovered until autopsy [ 5,6 ].
 All acute PE not meeting the definition of massive PE are considered submassive
PE.
Clinical syndromes – VTE…

 The presence of pulmonary infarction

 Usually indicates a small PE
 Is exquisitely painful because it lodges peripherally,
near the innervation of pleural nerves.

 Pleuritic chest pain is more common with small,

peripheral emboli.
.

 Nonthrombotic PE may be easily overlooked.

 Possible etiologies include:
 Fat embolism after pelvic or long bone fracture,
 Tumor embolism,

 Bone marrow, and air embolism.

 Cement embolism and bony fragment embolism can occur after total hip or knee
replacement.

 IV drug users may inject themselves with a wide array of substances that can
embolize such as hair, talc, and cotton.

 Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental
margin.
18
 C/Fs PE

 Dyspnea is the most common symptom of PE, and

 Tachypnea is the most common sign.

 Dyspnea, syncope, hypotension, or cyanosis indicates a massive PE

 Whereas pleuritic pain, cough, or hemoptysis often suggests a small
embolism situated distally near the pleura.

 On P/E, young and previously healthy individuals may appear

anxious but otherwise seem well.
 They may have dyspnea only with moderate exertion.
 Often lack "classic" signs such as tachycardia, low-grade fever, neck vein
distention, and an accentuated P2.
Saddle PE is a PE that lodges at the bifurcation of the
main pulmonary artery into the right and left
pulmonary arteries. saddle PE are usually submassive
and appear to have a similar response to therapy as
other types of PE, with a mortality rate of 5.4 percent.
 outine laboratory findings are nonspecific. They include
leukocytosis, an increased erythrocyte sedimentation rate
(ESR), and an elevated serum LDH or AST (SGOT) with a
normal serum bilirubin.
 Arterial blood gas  — Arterial blood gas (ABG)
measurements and pulse oximetry have a limited role in
diagnosing PE [ 2 ]. ABGs usually reveal hypoxemia,
hypocapnia, and respiratory alkalosis. Patients with room
air pulse oximetry readings <95 percent at the time of
diagnosis are at increased risk of in-hospital complications,
including respiratory failure, cardiogenic shock, and death
Nonimaging Diagnostic Modalities

 Blood Tests
 The quantitative plasma d-dimer rises in the presence of DVT or PE because of
the breakdown of fibrin by plasmin.
 The sensitivity of the d-dimer is >80% for DVT and >95% for PE.

 The d-dimer is a useful "rule out" test.

 The d-dimer assay is not specific.

 Levels increase in patients with myocardial infarction, pneumonia, sepsis,

cancer, and the postoperative state and pregnancy.

 Arterial blood gases lack specificity for PE, even though both PO2 and
Pco2 often decrease.

 PO2 & alveolar-arterial O2 gradient may help asses severity of PE.

20
 D-dimer  — D-dimer is a degradation product of cross-linked fibrin. It
can be detected in serum using a variety of different assays
 Enzyme-linked immunosorbent assay (ELISA) (results in >8 hrs)
 Quantitative rapid ELISA (results in 30 min)
 Semi-quantitative rapid ELISA (results in 10 min)
 Qualitative rapid ELISA (results in 10 min)
 Quantitative latex agglutination assay (results in 10 to 15 min)
 Semi-quantitative latex agglutination assay (results in 5 min)
 Erythrocyte agglutination assay (SimpliRED) (results in 2 min)

For the quantitative assays, a level >500 ng/mL is usually considered

abnormal
 PE & DVT - Dx…

 Elevated Cardiac Biomarkers

 Serum troponin levels increase b/ce of RV microinfarction.
 Myocardial stretch results in elevation of BNP or NT-pro-BNP.

 Biomarkers predict an increase in complications and mortality from PE.

 Electrocardiogram
 Sinus tachycardia is the most common
 The S1Q3T3 sign: an S wave in lead I, a Q wave in lead III, and an
inverted T wave in lead III.
 This finding is relatively specific but insensitive.
 Perhaps the most common finding is T-wave inversion in leads V1 to V4.

 Noninvasive Imaging Modalities

 Venous Ultrasonography for DVT
Limitations — Compression ultrasonography has several limitations.

It does not detect isolated thrombi in the iliac vein or that portion of the
femoral vein within the adductor canal .
As with impedance plethysmography, the results are limited in patients
with deformities or a plaster cast.
Serial studies need to be performed when the initial test is negative;
approximately 2 percent of patients with an initially negative ultrasound
develop a positive study when retested seven days later . A single repeat
study that is negative five to seven days after an initial negative study
predicts a less than 1 percent likelihood of venous thromboembolism over
months of follow-up .
Patients with pelvic neoplasms or abscesses may demonstrate isolated
noncompressibility of the femoral vein when thrombosis is absent
 PE & DVT - Dx…

 Because DVT and PE are so closely related and are both treated with
anticoagulation confirmed DVT is usually an adequate surrogate for
PE.

 In contrast, a normal venous ultrasound does not exclude PE.

 About one-half of patients with PE have no imaging evidence of

DVT

 For patients with nondiagnostic venous ultrasound, one should

consider alternative imaging modalities for DVT, such as CT and
MRI.
 CXR & Chest CT In PE

Chest Roentgenography
A normal CXR often occurs in PE.
 Well-established abnormalities include
 Focal oligemia (Westermark's sign),
 A peripheral wedged-shaped density above the diaphragm (Hampton's hump),
 An enlarged right descending pulmonary artery (Palla's sign).

Chest CT
 Spiral chest CT with IV contrast is the principal imaging test in PE.
 RV and LV enlargement can also be seen on CT and can be used for risk
stratification
 In PE, RV enlargement indicates an increased likelihood of death in the next 30 days.

 Lung parenchyma can be evaluated for alternative Dx such as pneumonia,

emphysema, pulmonary fibrosis, pulmonary mass, and aortic pathology.
 Sometimes asymptomatic early-stage lung cancer is diagnosed incidentally.
 Chest radiography  — Radiographic abnormalities are
common in patients with PE; however, they are not helpful
diagnostically because they are similarly common in patients
without PE. This was illustrated by a prospective study [ 4,17 ]:
 Atelectasis or a pulmonary parenchymal abnormality was noted
in 69 and 58 percent of patients with and without PE,
respectively.
 Pleural effusion was detected in 47 and 39 percent of patients
with and without PE, respectively.
 Only 12 percent of the chest radiographs in patients with PE
were interpreted as normal.
CT
which used predominantly
4-MD technology and a composite reference standard, demonstrated
sensitivity for the diagnosis of PE of 83%, specificity of 96%,
positive predictive value of 86%, and negative predictive value of 97%
Most patients with PE have abnormal but nonspecific chest radiographic
findings.Common radiographic findings include atelectasis,
pleural effusion, pulmonary infiltrates, and mild elevation of a
hemidiaphragm. Classic findings of pulmonary infarction – such
as Hampton’s hump or decreased vascularity (Westermark sign) – are
suggestive but infrequent. There is some confusion about the diagnostic
configuration of infiltrates due to embolism. These infiltrates,
although usually abutting a pleural surface, can be of any shape, not
necessarily wedge shaped. Although pleural effusions occur in almost
half of the patients, the majority of effusions are small and involve
only blunting of the costophrenic angle. The main use of the chest
radiograph in suspected PE is to exclude alternative diagnostic possibilities
such as pneumothorax, which may simulate the disease
Large bilateral proximal PE
On a coronal chest CT image in a 54/M with lung ca & brain metastases.
There are filling defects in the main & segmental pulmonary arteries bilaterally
(white arrows).
Only the left upper lobe segmental artery is free of thrombus.
 Lung Scanning In PE

 Albumin labeled with a gamma-emitting radionuclide are injected IV and are

trapped in the pulmonary capillary bed for perfusion scan.
 The perfusion scan defect indicates absent or decreased blood flow, possibly due to
PE.

 Ventilation scans, obtained with a radiolabeled inhaled gas such as xenon ,

improve the specificity of the perfusion scan.
 Abnormal ventilation scans indicate abnormal nonventilated lung, thereby providing
possible explanations for perfusion defects other than acute PE, such as asthma and
COPD.

 A high-probability scan for PE is defined as :A high-probability scan for PE is

defined as
 two or more segmental perfusion defects in the presence of normal ventilation
 One that indicates segmental perfusion defects
 In the presence of normal ventilation.
The diagnosis of PE is very unlikely in patients with normal and nearly normal scans
and is about 90% certain in patients with high-probability scans
fewer than one-half of patients with angiographically confirmed PE have a high
probability scan. As many as 40% of patients with high clinical suspicion for PE but
“lowprobability” scans do, in fact, have PE at angiography.
  A formal clinical probability algorithm was not used [ 23 ]:
 Patients with high clinical probability of PE and a high-probability V/Q scan had a
95 percent likelihood of having PE
 Patients with low clinical probability of PE and a low-probability V/Q scan had
only a 4 percent likelihood of having PE
 A normal V/Q scan virtually excluded PE
 Unfortunately, the combinations of clinical and lung scan probability that was
found in most patients had a diagnostic accuracy of only 15 to 86 percent , which is
insufficient to either confirm or exclude the diagnosis of PE
There are certain situations in which V/Q scanning may be
preferred over CT-pulmonary angiography (CT-PA). IV contrast is
not required for V/Q scanning making it a more desirable option
in patients with renal dysfunction or a severe iodinated contrast
allergy. In addition, with a portable gamma scintillation camera
the perfusion portion of the study can be performed at the bedside,
which may be a major advantage in a critically ill patient for whom
transportation to the CT scanner may be deemed too high risk. The
role of V/Q scanning versus CT-PA in pregnancy remains unsettled
but V/Q scanning appears to offer similar diagnostic performance
in this setting with significantly lower levels of maternal radiation.
-
 MRI (Contrast-Enhanced)
 When ultrasound is equivocal, MR venography with gadolinium contrast is an excellent
imaging modality to diagnose DVT.

Echocardiography
 Most patients with PE have normal echocardiograms.

 However, echocardiography can detect conditions that may mimic PE, such as

AMI , pericardial tamponade, and aortic dissection.

 Transthoracic echocardiography rarely images thrombus directly.

 The best-known indirect sign of PE on transthoracic echocardiography is hypokinesis of
the RV free wall.

 Transesophageal echocardiography when CT scanning facilities are not available

or when a patient has renal failure or severe contrast allergy.
 This imaging modality can identify saddle, right main, or left main PE.
Transthoracic echocardiography rarely images thrombus directly. The
best-known indirect sign of PE on transthoracic echocardiography
is McConnell’s sign: hypokinesis of the RV free wall with normal
or hyperkinetic motion of the RV apex. One should consider transesophageal
echocardiography when CT scanning facilities are not
available or when a patient has renal failure or severe contrast allergy
that precludes administration of contrast despite premedication with
high-dose steroids. This imaging modality can identify saddle, right
main, or left main PE.
 Echocardiography  — Only 30 to 40 percent of patients with PE have
echocardiographic abnormalities suggestive of acute PE
 Increased right ventricular (RV) size
 Decreased RV function
 Tricuspid regurgitation
 In cases of massive PE, however, these abnormalities are more likely and
echocardiography may be useful if a rapid presumptive diagnosis is required to
justify the use of thrombolytic therapy
 Additional echocardiographic findings suggestive of PE include:
 RV thrombus. The incidence of PE among patients with an RV thrombus appears
to be >35 percent . However, only 4 percent of patients with PE have an RV
thrombus
 Regional wall motion abnormalities that spare the right ventricular apex
("McConnell's sign")
Invasive Diagnostic Modalities - VTE

Pulmonary Angiography

 Invasive catheter-based diagnostic testing is reserved

 For patients with technically unsatisfactory chest CTs and
 Those in whom an interventional procedure such as catheter-directed
thrombolysis or embolectomy is planned.

 A definitive diagnosis of PE depends on visualization of an intraluminal

filling defect.

Contrast Phlebography for DVT

 Venous ultrasonography has virtually replaced contrast phlebography as

the diagnostic test for suspected DVT.
 The following eight factors constitute the PE rule-out criteria (PERC):
 Age less than 50 years

 Heart rate less than 100 bpm

 Oxyhemoglobin saturation ≥95 percent

 No hemoptysis

 No estrogen use

 No prior DVT or PE

 No unilateral leg swelling

 No surgery or trauma requiring hospitalization within the past four weeks

Acute PE can probably be excluded without further diagnostic testing if the patient
meets all PERC criteria AND there is a low clinical suspicion for PE, according to
either the Wells criteria or a low gestalt probability determined by the clinician prior
to diagnostic testing for PE. This approach has been best studied in the emergency
department.
Treatment: Deep Venous Thrombosis

Primary Therapy versus Secondary Prevention

 Primary therapy consists of clot dissolution with thrombolysis or removal of PE
by embolectomy.
 Anticoagulation with heparin and warfarin or placement of an inferior vena
caval filter constitutes secondary prevention of recurrent PE.

Risk Stratification
 High-risk patients:
 Hemodynamic instability,
 RV dysfunction, RV enlargement, or
 Elevation of the troponin level due to RV microinfarction.

 Predictors of an increased mortality rate from PE:

 RV hypokinesis on echocardiography, RV enlargement on chest CT, and
 Troponin elevation
 Primary therapy should be reserved for patients at high risk of an adverse
clinical outcome.
dvt
PRIMARY THERAPY
Primary therapy consists of clot dissolution with pharmacomechanical
therapy that usually includes low-dose catheter-directed
thrombolysis. This approach is reserved for patients with extensive
femoral, iliofemoral, or upper extremity DVT. The open vein hypothesis
postulates that patients who receive primary therapy will
sustain less long-term damage to venous valves, with consequent
lower rates of postthrombotic syndrome
SECONDARY PREVENTION
Anticoagulation or placement of an inferior vena caval filter constitutes
secondary prevention of VTE. To lessen the severity of postthrombotic
syndrome of the legs, below-knee graduated compression
stockings may be prescribed, 30–40 mmHg, for 2 years after the
DVT episode. They should be replaced every 3 months because they
lose their elasticity.
Acute management of pulmonary
thromboembolism.
ANTICOAGULATION

Effective anticoagulation is the foundation for successful treatment

of DVT and PE. There are three options: (1) the conventional strategy of parenteral
therapy “bridged” to warfarin, (2) parenteral therapy
“bridged” to a novel oral anticoagulant such as dabigatran (a direct
thrombin inhibitor) or edoxaban (an anti-Xa agent), or (3) oral anticoagulation
with rivaroxaban or apixaban (both are anti-Xa agents)
with a loading dose followed by a maintenance dose as monotherapy
without parenteral anticoagulation.
The three heparin-based parenteral anticoagulants are
(1) unfractionated heparin (UFH), (2) low-molecular-weight heparin
(LMWH), and (3) fondaparinux. For patients with suspected or
proven heparin-induced thrombocytopenia, there are two parenteral
direct thrombin inhibitors: argatroban and bivalirudin
(ACCP) guidelines recommend considerin anticoagulation for an indefinite
duration with a target INR between
2 and 3 for patients with idiopathic VTE. An alternative approach
after the first 6 months of anticoagulation is to reduce the intensity
of anticoagulation and to lower the target INR range to between
1.5 and 2.
Counterintuitively, the presence of genetic mutations such as
heterozygous factor V Leiden and prothrombin gene mutation does
not appear to increase the risk of recurrent VTE. However, patients
with antiphospholipid antibody syndrome may warrant indefiniteduration
anticoagulation, even if the initial VTE was provoked by
trauma or surgery
One commonly employed dosing regimen
using an initial intravenous bolus of 80 units of heparin per kilogram
followed by a continuous infusion initiated at 18 U/kg/h has been
demonstrated to reach therapeutic thresholds more quickly than
regimens using fixed dosing.88 The heparin drip is adjusted based
on monitoring of the aPTT, drawn 6 hours after the initial bolus dose,
then 6 hours after each dose adjustment, with a target aPTT ratio of
1.5 to 2.5.
More recently, an approach using a fixed dose of subcutaneous
unfractionated heparin without aPTT monitoring, administered
as an initial dose of 333 U/kg followed by a dose of 250 U/kg every
12 hours, has been demonstrated to be as safe and effective as
LMWH in patients presenting with DVT and PE
In general, therapeutic monitoring is not needed with LMWH,
but there are situations where the therapeutic effects may be less
predictable and monitoring with anti-Xa levels is indicated. Typical
examples include (1) patients with antiphospholipid antibodies
or other circulating anticoagulants who have elevated baseline
aPTT; (2) extremes of body weight (less than 40 kg and greater
than 150 kg); (3) significant renal disease (creatinine clearance less
than 30 mL/min); (4) pregnancy; and (5) unexplained bleeding or
recurrent thrombosis during therapy. A therapeutic target range
for peak anti-Xa levels ranges from 0.6 to 1.0 IU/mL, 4 hours after
administration. The target range for peak anti-Xa levels with once
daily enoxaparin is likely to be greater than1.0 IU/mL whereas it is
greater than 0.85 IU/mL with tinzaparin and 1.3 IU/mL and 1.05
IU/mL with nadroparin and dalteparin, respectively
INFERIOR VENA CAVAL (IVC) FILTERS

The two principal indications for insertion of an IVC filter are

(1) active bleeding that precludes anticoagulation and (2) recurrent
venous thrombosis despite intensive anticoagulation. Prevention of
recurrent PE in patients with right heart failure who are not candidates
for fibrinolysis and prophylaxis of extremely high-risk patients
are “softer” indications for filter placement. The filter itself may fail
by permitting the passage of small-to medium-size clots. Large
thrombi may embolize to the pulmonary arteries via collateral veins
that develop. A more common complication is caval thrombosis
with marked bilateral leg swelling
Paradoxically, by providing a nidus for clot formation, filters
increase the DVT rate, even though they usually prevent PE (over
the short term). Retrievable filters can now be placed for patients
with an anticipated temporary bleeding disorder or for patients at
temporary high risk of PE, such as individuals undergoing bariatric
surgery who have a prior history of perioperative PE. The filters can
be retrieved up to several months after insertion unless thrombus
forms and is trapped within the filter. The retrievable filter becomes
permanent if it remains in place or if, for technical reasons such as
rapid endothelialization, it cannot be removed
MANAGEMENT OF MASSIVE PE

For patients with massive PE and hypotension, replete volume with

500 mL of normal saline. Additional fluid should be infused with
extreme caution because excessive fluid administration exacerbates
RV wall stress, causes more profound RV ischemia, and worsens LV
compliance and filling by causing further interventricular septal shift
toward the LV. Dopamine and dobutamine are first-line inotropic
agents for treatment of PE-related shock. Maintain a low threshold
for initiating these pressors. Often, a “trial-and-error” approach works
best; other agents that may be effective include norepinephrine,
vasopressin, or phenylephrine.
Treatment: Massive Pulmonary Embolism

Anticoagulation

 Immediately effective anticoagulation is initiated with a parenteral drug: UFH,

LMWH, or fondaparinux.

 In patients with heparin-induced thrombocytopenia - A direct thrombin

inhibitor (argatroban, lepirudin, or bivalirudin )

 Parenteral agents are continued as a transition or "bridge" to stable, long-term

anticoagulation with a vitamin K antagonist (warfarin).

 Warfarin requires 5–7 days to achieve a therapeutic effect.

 During that period , overlap the parenteral and oral agents.

 After 5–7 days of anticoagulation, residual thrombus begins to endothelialize in

the vein or pulmonary artery.
FIBRINOLYSIS

Successful fibrinolytic therapy rapidly reverses right heart failure

and may result in a lower rate of death and recurrent PE by
(1) dissolving much of the anatomically obstructing pulmonary arterial
thrombus, (2) preventing the continued release of serotonin and
other neurohumoral factors that exacerbate pulmonary hypertension,
and (3) lysing much of the source of the thrombus in the pelvic
or deep leg veins, thereby decreasing the likelihood of recurrent PE.
The preferred fibrinolytic regimen is 100 mg of recombinant
tissue plasminogen activator (tPA) administered as a continuous
peripheral intravenous infusion over 2 h. The sooner thrombolysis is
administered, the more effective it is. However, this approach can be
used for at least 14 days after the PE has occurred
The only Food and Drug Administration–approved indication for
PE fibrinolysis is massive PE. For patients with submassive PE, who
have preserved systolic blood pressure but moderate or severe RV
dysfunction, use of fibrinolysis remains controversial.
PHARMACOMECHANICAL CATHETER-DIRECTED THERAPY

Many patients have relative contraindications to full-dose thrombolysis.

Pharmacomechanical catheter-directed therapy usually
combines physical fragmentation or pulverization of thrombus with
catheter-directed low-dose thrombolysis. Mechanical techniques
include catheter maceration and intentional embolization of clot
more distally, suction thrombectomy, rheolytic hydrolysis, and lowenergy
ultrasound-facilitated thrombolysis. The dose of alteplase
can be markedly reduced, usually to a range of 20 to 25 mg instead
of the peripheral intravenous systemic dose of 100 mg
PULMONARY EMBOLECTOMY

The risk of major hemorrhage with systemically administered fibrinolysis

has prompted a renaissance of interest in surgical embolectomy,
an operation that had almost become extinct. More rapid
referral before the onset of irreversible multisystem organ failure
and improved surgical technique have resulted in a high survival
rate
PULMONARY THROMBOENDARTERECTOMY

Chronic thromboembolic pulmonary hypertension develops in

2–4% of acute PE patients. Therefore, PE patients who have initial
pulmonary hypertension (usually diagnosed with Doppler echocardiography)
should be followed up at about 6 weeks with a repeat
echocardiogram to determine whether pulmonary arterial pressure
has normalized. Patients impaired by dyspnea due to chronic
thromboembolic pulmonary hypertension should be considered
for pulmonary thromboendarterectomy, which, if successful, can
markedly reduce, and sometimes even cure, pulmonary hypertension
EMOTIONAL SUPPORT

Patients with VTE may feel overwhelmed when they learn that they
are suffering from PE or DVT. Some have never previously
encountered
serious cardiovascular illness. They wonder whether they will
be able to adapt to the new limitations imposed by anticoagulation.
They worry about the health of their families and the genetic
implications of their illness. Those who are advised to discontinue
anticoagulation may feel especially vulnerable about the potential
for suffering recurrent VTE.
Unfractionated Heparin

 UFH anticoagulates by binding to and accelerating the activity of

antithrombin.

 UFH is dosed to achieve a target activated partial thromboplastin

time (aPTT) that is 2–3 times the upper limit of the laboratory
normal.
 This is usually equivalent to an aPTT of 60–80 s.

 The major advantage of UFH is its short half-life.

 This is especially useful if the patient may undergo an invasive procedure
such as embolectomy.

 Patients are at risk of developing heparin-induced thrombocytopenia.

Low-Molecular-Weight Heparins

 These fragments of UFH have greater

bioavailability, a more predictable dose
response, and a longer half-life than does UFH.

 No monitoring or dose adjustment is needed

unless the patient is markedly obese or has
chronic kidney disease.
Warfarin

 This vitamin K antagonist prevents carboxylation activation of

coagulation factors II, VII, IX, and X.

 Overlapping UFH, LMWH, or fondaparinux with warfarin for

at least 5 days can counteract the early procoagulant effect of
unopposed warfarin.

 In an average-size adult, warfarin usually is initiated in a dose

of 5 mg

 The target INR is usually 2.5, with a range of 2.0–3.0.

Use of warfarin
without heparin is strongly discouraged as it generally takes 3 to 5
days of warfarin to achieve full therapeutic efficacy. In patients with
protein C deficiency, skin necrosis or paradoxical thrombosis may
occur in the absence of concurrent heparin therapy.
Another rare complication of warfarin use is cholesterol
microembolism (“purple toes” syndrome), which is thought
to be due to cholesterol crystal release from ulcerated intravascular
plaques
Individuals metabolize warfarin differently and age, genetic
variations in CYP2C9 alleles, nutritional factors, and concomitant
medications can affect anticoagulant levels significantly. Multiple
mechanisms of drug interaction are possible including alterations of
absorption (cholestyramine), induction of hepatic CYP450 (barbiturates,
carbamazepine), inhibition of CYP3A4 (amiodarone), inhibition
of CYP2C9 (metronidazole, clotrimazole), and displacement
of protein-bound warfarin (phenytoin).
Complications of Anticoagulants

 Hemorrhage.
 For life-threatening or intracranial hemorrhage due to heparin or LMWH,
protamine sulfate can be administered.

 There is no specific antidote for bleeding caused by fondaparinux or direct

thrombin inhibitors.

 Major bleeding from warfarin is best managed with prothrombin complex

concentrate.
 With non-life threatening bleeding in a patient who can tolerate large volume, fresh-
frozen plasma can be used.
 Recombinant human coagulation factor VIIa (rFVIIa), is an option to manage
catastrophic bleeding from warfarin.
 For minor bleeding or to manage an excessively high INR in the absence of bleeding,
oral vitamin K may be administered.
 Complications of Anticoagulants…

 HIT and osteopenia are far less common with LMWH than with
UFH.

 Thrombosis due to HIT should be managed with a direct

thrombin inhibitor:
 Argatroban for patients with renal insufficiency and
 Lepirudin for patients with hepatic failure.

 During pregnancy, warfarin should be avoided if possible because

of warfarin embryopathy,
 Most common during the 6th through 12th week of gestation.

 However, women can take warfarin postpartum and breast-feed safely.

 Warfarin can also be administered safely during the second trimester.
Duration of Anticoagulation

 Patients with PE after surgery, trauma, or estrogen exposure ordinarily

have a low rate of recurrence after 3–6 months of anticoagulation.

 For DVT isolated to an upper extremity or calf that has been provoked
by surgery, trauma, estrogen, or an indwelling central venous catheter
or pacemaker, 3 months of anticoagulation suffices.

 For provoked proximal leg DVT or PE, 3 to 6 months of anticoagulation

is sufficient.

 For patients with cancer and VTE, the consensus is to prescribe 3–6
months of LMWH as monotherapy without warfarin and
 To continue anticoagulation indefinitely unless the patient is rendered cancer-
free.
Duration of Anticoagulation…

 Among patients with idiopathic, unprovoked

VTE, the recurrence rate is high after cessation
of anticoagulation

 It is recommended that anticoagulation be

considered for an indefinite duration with a
target INR b/n 2 and 3 for patients with
idiopathic VTE.
Maintaining Adequate Circulation

 For patients with massive PE and hypotension, one should

administer 500 mL of normal saline.

 Dopamine and dobutamine are first-line inotropic agents for

treatment of PE-related shock.

 There should be a low threshold for initiating these pressors.

 Consider also norepinephrine, vasopressin, or phenylephrine.

Prevention of Postphlebitic Syndrome

 Daily use of below-knee 30- to 40-mmHg vascular

compression stockings will halve the rate of developing
postphlebitic syndrome.

 These stockings should be prescribed as soon as DVT is

diagnosed

 When patients are in bed, the stockings need not be worn.

-
-
Prevention of Venous Thromboembolism

Condition Prophylactic strategy

High-risk general surgery Mini-UFH or LMWH

Thoracic surgery Mini-UFH + IPC

Cancer surgery, including LMWH, consider 1 month of prophylaxis

gynecologic cancer surgery

Total hip replacement, total knee LMWH, fondaparinux 2.5 mg SC, once daily,
replacement, hip fracture surgery or (except for total knee replacement) warfarin
(target INR 2.5);
Prevention of Venous Thromboembolism…

Condition Prophylactic Strategy

Neurosurgery IPC

Neurosurgery for brain tumor Mini-UFH or LMWH, + IPC + predischarge

venous ultrasonography

Benign gynecologic surgery Mini-UFH

Medically ill patients Mini-UFH or LMWH

Anticoagulation contraindicated IPC