Venous Thromboembolism

(VE)- Deep Vein Thrombosis

(DVT) and Pulmonary Embolus
(PE)
Victoria E. Judd M.D.
 Objectives
• Discuss common presentation of Deep Vein
Thrombosis (DVT) and Pulmonary
Embolism (PE)
• Describe evidence-based diagnostic and
therapeutic strategies for DVT/PE
• Identify when to screen for a
hypercoaguable state
 Causes of Thromboembolism
• Inherited
• Acquired
 Inherited VE
Inherited thrombophilia
• Factor V Leiden mutation
• Prothrombin gene mutation
• Protein S deficiency
• Protein C deficiency
• Antithrombin (AT) deficiency
• Rare disorders
• Dysfibrinogenemia
 Other Plasma Factors
• In a single, large, population-
based case control study
performed in the Netherlands, a
two to threefold increased risk for
a first episode of venous
thrombosis was found for elevated
levels of a number of plasma
components, coagulant factors,
and inflammatory chemokines.
 Other Plasma Factors
• Plasma factor IX antigen
• Plasma factor XI antigen
• Thrombin activatable fibrinolysis inhibitor
(TAFI)
• Interleukin 8
• Fibrinogen
• Low levels of tissue factor pathway inhibitor
• Low plasma fibrinolytic activity
• Elevated plasma fibronectin levels
 Acquired VE
• Malignancy
• Presence of a central venous catheter
• Surgery, especially orthopedic
• Trauma
• Pregnancy
• Oral contraceptives
• Hormone replacement therapy
 Categories of risk for venous
thromboembolism in surgical patients

Low risk:
Minor surgery in patients <40
years of age with no additional risk
factors present*
• Risk of calf DVT: 2 percent
• Risk of proximal DVT: 0.4 percent
• Risk of clinical PE: 0.2 percent
• Risk of fatal PE: <0.01 percent
 Categories of risk for venous
thromboembolism in surgical patients

Moderate risk:
Minor surgery in patients with additional
risk factor present*, or
Surgery in patients aged 40-60 with no
additional risk factor
• Risk of calf DVT: 10-20 percent
• Risk of proximal DVT: 2-4 percent
• Risk of clinical PE: 1-2 percent
• Risk of fatal PE: 0.1-0.4 percent
 Categories of risk for venous
thromboembolism in surgical patients

High risk:
Surgery in patients >60, or
Surgery in patients aged 40-60 with
additional risk factor*
• Risk of calf DVT: 20-40 percent
• Risk of proximal DVT: 4-8 percent
• Risk of clinical PE: 2-4 percent
• Risk of fatal PE: 0.4-1.0 percent
 Categories of risk for venous
thromboembolism in surgical patients

Highest risk:
Surgery in patients >40 with multiple risk
factors*, or
Hip or knee arthroplasty, hip fracture
surgery, or
Major trauma, spinal cord injury
• Risk of calf DVT: 40-80 percent
• Risk of proximal DVT: 10-20 percent
• Risk of clinical PE: 4-10 percent
• Risk of fatal PE: 0.2-5 percent
 Categories of risk for venous
thromboembolism in surgical patients

• * Additional risk factors include one or

more of the following: advanced age,
cancer, prior venous thromboembolism,
obesity, heart failure, paralysis, or
presence of a molecular
hypercoagulable state (e.g., protein C
deficiency, factor V Leiden).

• Data from Geerts, WH, et al. Chest 2004; 126:3385.

 Acquired VE
• Oral contraceptive pills that contain third-
generation progestins are the most important
cause of thrombosis in young women.
• The risk of thrombosis increases within four
months of the initiation of therapy and is
unaffected by duration of use.
• The risk decreases to previous levels within
three months of cessation.
• An increased risk for VTE has also been found
in women using contraceptive transdermal
patches and ring.
 Acquired VE
• Tamoxifen, Bevacizumab, Thalidomide,
Lenalidomide
• Immobilization
• Congestive failure
• Antiphospholipid antibody syndrome
• Myeloproliferative disorders
• Polycythemia vera
• Essential thrombocythemia
• Paroxysmal nocturnal hemoglobinuria
 Acquired VE
• Inflammatory bowel disease
• Nephrotic syndrome
• Hyperviscosity
• Waldenstrom's macroglobulinemia
• Multiple myeloma
• Marked leukocytosis in acute leukemia
• Sickle cell anemia
• HIV/AIDS
 Causes of Thromboembolism
• Fifty percent of thrombotic events
in patients with inherited
thrombophilia are associated with
the additional presence of an
acquired risk factor (e.g., surgery,
prolonged bed rest, pregnancy,
oral contraceptives).
 Causes of Thromboembolism
• Some patients have more than one
form of inherited thrombophilia or
more than one form of acquired
thrombophilia and appear to be at
even greater risk for thrombosis.
 Causes of Thromboembolism
• In a population-based study of the
incidence of venous
thromboembolism (VTE), 56
percent of the patients had three
or more of the following six risk
factors present at the time of VTE:
 Causes of Thromboembolism
• >48 hours of immobility in the
preceding month
• Hospital admission
• Surgery
• Malignancy
• Infection in the past three months
• Current hospitalization
 Incidence of pulmonary embolism
according to distance traveled by air
 Incidence of pulmonary embolism
according to distance traveled by air

• This figure indicates the incidence of

pumonary embolism per million
passenger arrivals, arranged according
to flight distance in kilometers. Error
bars indicate 95 percent confidence
limits. To convert kilometers to miles,
multiply by 0.62.
• Data from Lapastolle, F, et al. N Engl J Med 2001;
345:779.
Seasonal variation in venous
thromboembolism
 Seasonal variation in venous
thromboembolism

• Depicted are the monthly percentage

variations in French hospital admissions for
deep vein thrombosis and pulmonary
embolism. Hospital admissions for venous
thromboembolism were most frequent in the
winter and least frequent in the summer.
• Reproduced with permission from: Boulay, F, Berthier,
F, Schoukroun, G, et al. Seasonal variations in hospital
admission for deep venous thrombosis and pulmonary
embolism: analysis of discharge data. BMJ 2001;
323:601. Copyright © 2001, BMJ.
 Risks Factors for DVT
• The risk of thrombosis is increased in all
forms of major injury.
• In one study of 716 patients admitted
to a regional trauma unit, DVT in the
lower extremities was found in 58
percent of patients with adequate
venographic studies; 18 percent had
proximal vein thrombosis.
 Risks factors for DVT
Thrombi were detected in:
• 54 percent of patients with major head
injuries
• 61 percent of patients with pelvic
fracture
• 77 percent of patients with tibial
fracture
• 80 percent of those with femoral
fracture.
 Risk Factors for DVT
• Minor injuries — A large population-based
study investigated the VTE risk following a
minor injury (i.e., one not requiring surgery,
a plaster cast, hospitalization, or extended
bed rest at home for at least four days).
• A minor injury occurring in the preceding 3
to 4 weeks was associated with a 3- to 5-
fold increase in DVT risk.
• In carriers of factor V Leiden, this risk was
increased 50-fold.
 Risks Factors for DVT
• Intravenous drug use — Direct
trauma, irritation, and infection
may be responsible for the high
incidence of DVT noted in young
drug users who inject these agents
directly into their femoral veins.
 Risk Factors for DVT
• Pregnancy — Pregnancy is associated
with an increased risk of thrombosis
that may be due in part to obstruction
of venous return by the enlarged
uterus, as well as the hypercoagulable
state associated with pregnancy.
• Estimates of the age-adjusted incidence
of VTE range from 5 to 50 times higher
in pregnant versus non-pregnant
women.
 Pathophysiology
• VIRCHOW'S TRIAD — A major theory
delineating the pathogenesis of venous
thromboembolism (VTE), often called
Virchow's triad, proposes that VTE occurs
as a result of:
• Alterations in blood flow (i.e., stasis)
• Vascular endothelial injury
• Alterations in the constituents of the
blood (i.e., inherited or acquired
hypercoagulable state)
 Deep Vein Thrombosis (DVT)
• The thrombotic risk associated
with the inherited thrombophilias
has been assessed in two ways:
evaluation of patients with deep
vein thrombosis, and evaluation of
families with thrombophilia.
 DVT
• In a Spanish study of 2132 consecutive
unselected patients with venous
thromboembolism, for example, 12.9
percent had an anticoagulant protein
deficiency (7.3 percent with protein S,
3.2 percent with protein C, and 0.5
percent with antithrombin). An
additional 4.1 percent had
antiphospholipid antibodies (aPL).
 Risks and incidence of a
first episode of venous
thrombosis

• Adult subjects only.

• Data from the Leiden
Thrombophilia Study.
Condition/risk factor(s) Relative Incidence, percent per year
risk

Normal 1 0.008
Hyperhomocysteinemia (MTHFR 677T
mutation)
2.5 0.02

Prothrombin gene mutation 2.8 0.02

Oral contraceptives 4 0.03
Factor V Leiden (heterozygous) 7 0.06
Oral contraceptives plus heterozygous 35 0.29
factor V Leiden

Factor V Leiden (homozygous) 80 0.5-1.0

 DVT
• Similar findings were noted in a series of
277 Dutch outpatients with deep vein
thrombosis: 8.3 percent had an isolated
deficiency of antithrombin, protein C,
protein S, or plasminogen compared to 2.2
percent of controls.
• The incidence of a protein deficiency was
only modestly greater in "high risk"
patients with recurrent, familial, or juvenile
onset deep vein thrombosis (9, 16, and 12
percent respectively).
 DVT
• The overall 8 to 13 percent incidence
of an isolated anticoagulant protein
deficiency in patients with deep vein
thrombosis does not include the
contribution of factor V Leiden or the
prothrombin gene mutation, now
considered to be the most common
causes of inherited thrombophilia.
 DVT
• The Physicians' Health Study and
the Leiden Thrombophilia Study
found a 12 to 19 percent incidence
of heterozygosity for the factor V
Leiden mutation in patients with a
first DVT (or pulmonary embolism
in the Physicians' Health Study)
compared to 3 to 6 percent in
controls.
 DVT
• The incidence reached 26 percent in the
Physicians' Health Study in 31 men over
the age of 60 with no identifiable
precipitating factors.
• The incidence of the prothrombin gene
mutation is approximately 6 to 8
percent in patients with deep vein
thrombosis compared to 2 to 2.5
percent in controls.
 DVT
• The total incidence of an inherited
thrombophilia in subjects with a deep
vein thrombosis ranges from 24 to 37
percent overall compared to about 10
percent in controls. Another 25 percent
of patients appear to have elevated
factor VIII levels, although it has not
been proven that this is an inherited
characteristic.
 DVT
• There are a number of questions
that arise when a patient is
suspected of having deep vein
thrombosis (DVT) of the lower
extremity.
 DVT
• What is the differential diagnosis
and what are the possible risk
factors for DVT?
• What is the best way to diagnose
or exclude DVT?
 DVT
• What is the appropriate initial
therapy for DVT; when is
hospitalization not required?
• What is the recommended long-
term treatment for DVT (e.g.,
agents to use, monitoring the
degree of anticoagulation, length
of time treatment is needed)?
 DVT
• When should one screen for the
presence of a hypercoagulable
state, not only in the patient, but
also in family members?
 DVT
INITIAL APPROACH
• When approaching the patient with
suspected DVT of the lower
extremity, it is important to
appreciate that only a minority of
patients actually have the disease
and will require anticoagulation.
 DVT
• This illustrates the importance of using
validated algorithms to evaluate patients
with suspected DVT, along with objective
testing to establish the diagnosis.
• Given the potential risks associated with
proximal lower extremity DVT that is not
treated (e.g., fatal pulmonary emboli) and
the potential risk of anticoagulating a
patient who does not have a DVT (e.g.,
fatal bleeding), accurate diagnosis is
essential.
 DVT History
• Classic symptoms of DVT include
swelling, pain, and discoloration in
the involved extremity.
• There is not necessarily a
correlation between the location of
symptoms and the site of
thrombosis.
 DVT History
• Symptoms in the calf alone are
often the presenting manifestation
of significant proximal vein
involvement, while some patients
with whole leg symptoms are
found to have isolated calf vein
DVT.
 DVT History
• A complete thrombosis history includes the
age of onset, location of prior thromboses,
and results of objective diagnostic studies
documenting thrombotic episodes in the
patient, as well as in any family members.
• A positive family history is particularly
important, since a well documented history
of venous thrombosis in one or more first-
degree relatives strongly suggests the
presence of a hereditary defect.
 DVT History
• Recent potential precipitating
conditions
• Underlying conditions: i.e. cancer,
collagen-vascular disorders
• Medications
 DVT Physical Exam
Special attention should be directed to:
• The vascular system
• Extremities (e.g., looking for signs of
superficial or deep vein thrombosis)
• Chest
• Heart
• Abdominal organs
• Skin (e.g., skin necrosis, livedo
reticularis).
 DVT Physical Exam
• There may be pain and tenderness
in the thigh along the course of the
major veins ("painful deep vein
syndrome").
• Tenderness on deep palpation of
the calf muscles is suggestive, but
not diagnostic.
• Homan's sign is unreliable.
 DVT Physical Exam
• A 2005 meta-analysis of diagnostic
cohort studies of patients with
suspected DVT concluded the following
concerning these physical findings:
• Only a difference in calf diameters
(likelihood ratio, LR 1.8; 95% CI 1.5-
2.2) was of potential value for ruling in
DVT.
 DVT Physical Exam
• Only absence of calf swelling (LR 0.67;
95% CI 0.58-0.78) and absence of a
difference in calf diameters (LR 0.57;
95% CI 0.44-0.72) were of potential
value for ruling out DVT
• Individual clinical features are poorly
predictive of DVT when not combined in
a formal prediction rule (e.g., Wells
score, see below).
 DVT Physical Exam
Many patients are asymptomatic; however, the
history may include the following:
• Edema, principally unilateral, is the most specific
symptom. Massive edema with cyanosis and
ischemia (phlegmasia cerulea dolens) is rare.
• Leg pain occurs in 50% of patients, but this is
entirely nonspecific. Pain can occur on
dorsiflexion of the foot (Homans sign).
 DVT Physical Exam
Homan’s sign
• Discomfort in the calf muscles on forced
dorsiflexion of the foot with the knee straight has
been a time-honored sign of DVT. However, this
sign is present in less than one third of patients
with confirmed DVT.
• The Homan’s sign is found in more than 50% of
patients without DVT and, therefore, is
nonspecific.
 DVT Physical Exam
-Tenderness occurs in 75% of patients but is also found in
50% of patients without objectively confirmed DVT.
-Clinical signs and symptoms of PE as the primary
manifestation occur in 10-50% of patients with
confirmed DVT.
-The pain and tenderness associated with DVT does not
usually correlate with the size, location, or extent of the
thrombus.
-Warmth or erythema of skin can be present over the area
of thrombosis
 DVT Physical Exam
o Superficial thrombophlebitis is characterized by
the finding of a palpable, indurated, cordlike,
tender, subcutaneous venous segment.
o Forty percent of patients with superficial
thrombophlebitis without coexisting varicose
veins and with no other obvious etiology (e.g.,
intravenous catheters, intravenous drug abuse, soft
tissue injury) have an associated DVT.
 DVT Differential Diagnosis
In one study of 160 consecutive
patients with suspected DVT who had
negative venograms, the following
causes of leg pain were identified:
• Muscle strain, tear, or twisting injury to
the leg — 40 percent
• Leg swelling in a paralyzed limb — 9
percent
 DVT Differential Diagnosis
• Lymphangitis or lymph obstruction
— 7 percent
• Venous insufficiency (reflux) — 7
percent
• Baker's cyst — 5 percent
• Cellulitis — 3 percent
• Knee abnormality — 2 percent
• Unknown — 26 percent
 DVT Diagnosis
• The clinical assessment of patients with
suspected DVT is often difficult because of
the interplay between risk factors and the
nonspecific nature of the physical findings.
• Clinicians have observed that a discordance
is often present between the clinical
assessment and the results of objective
testing.
 DVT Diagnosis
• One report of 593 patients with
suspected DVT validated a measure of
pretest probability in conjunction with
an algorithm designed to minimize the
use of venography or repeat
ultrasonography.
• The measure of pretest probability is
referred to as the Wells score or Wells
criteria for DVT probability:
 DVT Diagnosis
• The Wells clinical prediction guide quantifies the
pretest probability of DVT.
• The model enables providers to reliably stratify their
patients into high-, moderate-, or low-risk categories.
• Combining this with the results of objective testing
greatly simplifies the clinical workup of patients with
suspected DVT.
• The Wells clinical prediction guide incorporates risk
factors, clinical signs, and the presence or absence of
alternative diagnoses.
 DVT Diagnosis
• For example, patients deemed to be at high risk for
DVT may have a negative finding on duplex
ultrasonographic study.
• In this case, the probability of DVT is still greater
than 20% when the known sensitivity, specificity,
and negative likelihood ratio of duplex
ultrasonography are considered.
• Having an objective method to determine pretest
probability simplifies clinical management.
 Wells Score
• Paralysis, paresis, or recent orthopedic
casting of a lower extremity (1 point)
• Recently bedridden for longer than
three days or major surgery within the
past four weeks (1 point)
• Localized tenderness in the deep vein
system (1 point)
• Swelling of an entire leg (1 point)
 Wells Score
• Calf swelling 3 cm greater that the
other leg, measured 10 cm below
the tibial tuberosity (1 point)
• Pitting edema greater in the
symptomatic leg (1 point)
• Collateral non-varicose superficial
veins (1 point)
 Wells Score
• Active cancer or cancer treated
within six months (1 point)
• Alternative diagnosis more likely
than DVT (e.g., Baker's cyst,
cellulitis, muscle damage, post
phlebitic syndrome, inguinal
lymphadenopathy, external venous
compression (-2 points)
Clinical Parameter Score Score

Active cancer (treatment ongoing, or within 6 mo or palliative) +1

Paralysis or recent plaster immobilization of the lower extremities +1

Recently bedridden for >3 d or major surgery <4 wk +1

Localized tenderness along the distribution of the deep venous system +1

Entire leg swelling +1

Calf swelling >3 cm compared with the asymptomatic leg +1

Pitting edema (greater in the symptomatic leg) +1

Previous DVT documented +1

Collateral superficial veins (nonvaricose) +1

Alternative diagnosis (as likely or greater than that of DVT) -2

Total of Above Score

High probability >3

Moderate probability 1 or 2

Low probability <0

 Reference for Modified Wells
Score
• Adapted from JAMA. 1998 Apr 8;279(14):1094-9.

• Value of assessment of pretest probability of deep-vein thrombosis in clinical

management. Wells PS; Anderson DR; Bormanis J; Guy F; Mitchell M; Gray
L; Clement C; Robinson KS; Lewandowski B. Lancet 1997 Dec 20-
27;350(9094):1795-8.
 DVT Diagnosis
• DVT was documented in 3, 17, and 75
percent of patients with low, moderate,
and high pretest probabilities, respectively.
• Serial ultrasonography was required in 28
percent and venography in 6 percent of
patients; venous thromboembolism was
diagnosed during a three month follow-up
period in only 0.6 percent of patients
thought not to have a DVT by this
algorithm.
 DVT D-dimer
• Recent interest has focused on the use of D-dimer in the
diagnostic approach to DVT.
• D-dimer fibrin fragments are present in fresh fibrin clot
and in fibrin degradation products of cross-linked fibrin.
• Monoclonal antibodies specific for the D-dimer fragment
are used to differentiate fibrin-specific clot from non–
cross-linked fibrin and from fibrinogen.
• These specific attributes of the D-dimer antibodies account
for their high sensitivity for venous thromboembolism.
 DVT D-dimer
• D-dimer level may be elevated in any medical
condition where clots form.
• D-dimer level is elevated in trauma, recent
surgery, hemorrhage, cancer, and sepsis.
• Many of these conditions are associated with
higher risk for DVT.
• The D-dimer assays have low specificity for DVT;
therefore, they should only be used to rule out
DVT, not to confirm the diagnosis of DVT.
 Medical Conditions Associated
With an Elevated D-dimer
Arterial thromboembolic disease
• Myocardial infarction
• Stroke
• Acute limb ischemia
• Atrial fibrillation
• Intracardiac thrombus
 Medical Conditions Associated
With an Elevated D-dimer
Venous thromboembolic disease
• Deep vein thrombosis
• Pulmonary embolism
• Disseminated intravascular
coagulation
• Preeclampsia and eclampsia
Abnormal fibrinolysis; use of
thrombolytic agents
Medical Conditions Associated
With an Elevated D-dimer
Systemic inflammatory response
syndrome
Vasoocclusive episode of sickle cell
disease
Severe liver disease (decreased
clearance)
Malignancy
 Medical Conditions Associated
With an Elevated D-dimer
Renal disease
• Nephrotic syndrome (e.g., renal
vein thrombosis)
• Acute renal failure
• Chronic renal failure and underlying
cardiovascular disease
Normal pregnancy
Venous malformations
 DVT D-dimer
• D-dimer levels remain elevated in DVT for about 7
days.
• Patients presenting late in the course, after clot
organization and adherence have occurred, may have
low levels of D-dimer.
• Similarly, patients with isolated calf vein DVT may
have a small clot burden and low levels of D-dimer
that are below the analytic cut-off value of the assay.
• This accounts for the reduced sensitivity of the D-
dimer assay in the setting of confirmed DVT.
 DVT D-dimer
• Many different D-dimer assays are available, with varying
sensitivities and specificities.
• The assays are not standardized.
• They incorporate different monoclonal antibodies to the D-
dimer fragment.
• Results may be reported quantitatively or qualitatively.
• Different units may be used.
• Some assay results are reported as fibrinogen equivalent
units (FEU) and others in nanograms per milliliter (ng/mL).
• The results of one assay cannot be extrapolated to another.
 DVT D-dimer
• Most studies have confirmed the clinical
utility of D-dimer testing, and most clinical
algorithms incorporate their use.
• Providers should know their lab's D-dimer
assay
 DVT D-dimer
D-dimer results should be used as follows:
o A negative D-dimer assay result rules out DVT in
patients with low-to-moderate risk and a Wells
DVT score less than 2.
o All patients with a positive D-dimer assay result
and all patients with a moderate-to-high risk of
DVT (Wells DVT score >2) require a diagnostic
study (duplex ultrasonography).
 DVT D-dimer
• A D-dimer level less than 200 to
500 ng/mL by ELISA or a negative
SimpliRED assay in conjunction
with a low clinical probability of
DVT appears to be useful and cost-
effective in excluding DVT without
the need for an ultrasound
examination.
 DVT D-dimer
• This has been shown to hold in
populations at high risk of having
DVT, such as those with
malignancy, as well as in
populations in which the Wells
score and the D-dimer may have
reduced specificity, such as in the
elderly.
 DVT D-dimer
• The pretest probability of DVT is
determined from the Wells score
and a D-dimer test is performed.
 DVT D-dimer
• For those with a "low probability"
score and a negative D-dimer, DVT
is effectively ruled out.
• If the D-dimer test is positive,
ultrasound is performed to rule out
DVT.
 DVT D-dimer
• For those in whom DVT is likely (i.e.,
Wells score ≥1) ultrasound is performed
in all patients to rule out DVT.
• For the separate group in which the D-
dimer test was positive and the initial
ultrasound negative, a repeat
ultrasound is performed one week later
to rule out DVT.
 Limitations of the Wells Score
• A meta-analysis of 51 studies has
shown that the overall assessment
of clinical probability of DVT by use
of the Wells score is more useful
than any of the individual
components comprising the score,
with a negative likelihood ratio
(0.25, 95% CI 0.21-0.29) similar
to that of an empirical assessment.
 Limitations of the Wells Score
• Nevertheless, when the population to be
assessed contained a large percentage of
elderly patients or those with a prior DVT
or other comorbidities, as might occur in
a primary care setting, the performance
of the Wells criteria was reduced.
• Therefore, it seems prudent that the
Wells criteria are used to complement
rather than displace the clinician's
empirical assessment.
 Diagnosis of DVT
• In most circumstances, compression
ultrasonography is the noninvasive approach
of choice for the diagnosis of patients with
suspected DVT.
• If unavailable, impedance plethysmography
with serial studies is an acceptable alternative.
• One exception noted above is that impedance
plethysmography is preferred for possible
recurrent DVT since it normalizes more quickly
after a previous episode than compression
ultrasonography.
 Compression
Ultrasonography
The diagnosis of venous thrombosis
using compression ultrasonography is
made by the findings such as:
• Abnormal compressibility of the vein
• Abnormal Doppler color flow
• The presence of an echogenic band
• Abnormal change in diameter during the
Valsalva maneuver
 Compression
Ultrasonography
• Prospective studies have
demonstrated that lack of
compressibility of a vein with the
ultrasound probe is highly
sensitive (>95 percent) and
specific (>95 percent) for proximal
vein thrombosis.
 Compression
Ultrasonography
• Color flow imaging, in addition to
duplex Doppler ultrasound, is a
less demanding study and is also
highly accurate for the diagnosis of
above the knee DVT.
 Duplex-Doppler ultrasound image of an
acute superficial femoral vein thrombosis
(labeled "V")

Blue color indicates venous blood flow and red indicates

arterial blood flow (labeled "A"). Echogenic white
speckles are seen in the vein which was non-
compressible with the ultrasound probe.
 Compression
Ultrasonography
• In comparison, the presence of an
echogenic band, although sensitive for
DVT, has a specificity of only about 50
percent.
• The variation of venous size with the
Valsalva maneuver has a low sensitivity
and specificity for the presence of DVT
and is not performed in many centers.
 Compression
Ultrasonography
• 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.
 Compression
Ultrasonography
o Duplex ultrasonography is also helpful to
differentiate venous thrombosis from
hematoma, Baker cyst, abscess, and other
causes of leg pain and edema.
o Diagnostic accuracy varies depending on
local expertise.
 MRI
o MRI is the diagnostic test of choice for suspected
iliac vein or inferior vena caval thrombosis when
CT venography is contraindicated or technically
inadequate.
o In the second and third trimester of pregnancy,
MRI is more accurate than duplex ultrasonography
because the gravid uterus alters Doppler venous
flow characteristics.
o Expense, lack of general availability, and technical
issues limit its use.
 Screening For A Hypercoaguable State

• A biologic risk factor for venous thrombosis

can be identified in over 60 percent of
Caucasian patients with idiopathic DVT. In
addition, there is often more than one
factor at play in a given patient.
• As an example, 50 percent of thrombotic
events in patients with inherited
thrombophilia are associated with an
accompanying acquired risk factor (e.g.,
surgery, pregnancy, use of oral
contraceptives).
Screening For A Hypercoaguable State

• There is currently no consensus

regarding whom to test for
inherited thrombophilia.
• The likelihood of identifying an
inherited thrombophilia is
increased several-fold by screening
only patients with one or more of
the following:
Screening For A Hypercoaguable State

• Initial thrombosis occurring prior

to age 50 without an immediately
identified risk factor (i.e.,
idiopathic or unprovoked venous
thrombosis)
• A family history of venous
thromboembolism
Screening For A Hypercoaguable State

• Recurrent venous thrombosis

• Thrombosis occurring in unusual
vascular beds such as portal,
hepatic, mesenteric, or cerebral
veins
• A history of warfarin-induced skin
necrosis, which suggests protein C
deficiency
 Screening For A Hypercoaguable State

• Patients at increased risk for inherited

thrombophilia can be identified.
• There is no clear clinical value to
screening for the following reasons:
• Even if a hypercoagulable workup
uncovers abnormalities predisposing to
VTE, the strongest risk factor for VTE
recurrence is the prior VTE event itself,
particularly if idiopathic.
 Screening For A Hypercoaguable State

• Patients with idiopathic VTE, whether or not

they have an identifiable inherited
thrombophilia, are at high risk for
recurrence (as high as 7 to 8 percent per
year in some studies) after warfarin is
discontinued, at least for the first few years
after the event.
• Thus, the presence or absence of an
inherited thrombophilia will usually not
change the decision regarding length of
warfarin therapy.
Screening For A Hypercoaguable State

• Screening information can be used

to identify family members with an
inherited thrombophilia, but
anticoagulant prophylaxis is rarely
recommended in asymptomatic
affected family members outside of
high risk situations.
Screening For A Hypercoaguable State

Screening test interference —

• A number of factors can interfere
with screening tests for
thrombophilia.
• Therefore, it is generally best not
to undertake testing at the time of
presentation with VTE.
Screening For A Hypercoaguable State

Confounding Factors
• Acute thrombosis
• Heparin therapy
• Coumadin therapy
 Treatment of DVT
The primary objectives of
treatment of DVT are to prevent
and/or treat the following
complications:
• Prevent further clot extension
• Prevention of acute pulmonary
embolism
 Treatment of DVT
• Reducing the risk of recurrent thrombosis
• Treatment of massive iliofemoral
thrombosis with acute lower limb
ischemia and/or venous gangrene (i.e.,
phlegmasia cerulea dolens)
• Limiting the development of late
complications, such as the postphlebitic
syndrome, chronic venous insufficiency,
and chronic thromboembolic pulmonary
hypertension.
 Treatment of DVT
• Anticoagulant therapy is indicated
for patients with symptomatic
proximal DVT, since pulmonary
embolism will occur in
approximately 50 percent of
untreated individuals, most often
within days or weeks of the event.
 Treatment of DVT
• The use of thrombolytic agents, surgical
thrombectomy, or percutaneous
mechanical thrombectomy in the
treatment of venous thromboembolism
must be individualized.
• Patients with hemodynamically unstable
PE or massive iliofemoral thrombosis (i.e.,
phlegmasia cerulea dolens), and who are
also at low risk to bleed, are the most
appropriate candidates for such treatment.
 Treatment of DVT
• Inferior vena caval filter placement
is recommended when there is a
contraindication to, or a failure of,
anticoagulant therapy in an
individual with, or at high risk for,
proximal vein thrombosis or PE.
 Treatment of DVT
• It is also recommended in patients
with recurrent thromboembolism
despite adequate anticoagulation,
for chronic recurrent embolism
with pulmonary hypertension, and
with the concurrent performance
of surgical pulmonary
embolectomy or pulmonary
thromboendarterectomy.
 Treatment of DVT
• Oral anticoagulation with warfarin
should prolong the INR to a target of
2.5 (range: 2.0 to 3.0).
• If oral anticoagulants are
contraindicated or inconvenient, long-
term therapy can be undertaken with
either adjusted-dose unfractionated
heparin, low molecular weight heparin,
or fondaparinux.
 Treatment of DVT
• The general medical management
of the acute episode of DVT is
individualized.
• Once anticoagulation has been
started and the patient's symptoms
(i.e., pain, swelling) are under
control, early ambulation is
advised.
 Treatment of DVT
• During initial ambulation, and for
the first two years following an
episode of VTE, use of an elastic
compression stocking has been
recommended to prevent the
postphlebitic syndrome.
 PE classification
• Acute vs. chronic
• Massive vs. submassive
 PE Classification
• A saddle PE is a PE that lodges at the
bifurcation of the main pulmonary artery
into the right and left pulmonary arteries.
• Most saddle PE are submassive.
• In a retrospective study of 546
consecutive patients with PE, 14 (2.6
percent) had a saddle PE.
• Only two of the patients with saddle PE
had hypotension.
 PE Epidemiology
• In a study of more than 42 million deaths
that occurred over a 20-year duration,
almost 600,000 patients (approximately
1.5 percent) were diagnosed with PE.
• PE was the presumed cause of death in
approximately 200,000.
• This study certainly underestimates the
true incidence and prevalence of PE,
since more than half of all PE are
probably undiagnosed.
 PE Prognosis
• PE is associated with a mortality
rate of approximately 30 percent
without treatment, primarily due to
recurrent embolism.
• However, accurate diagnosis
followed by effective anticoagulant
therapy decreases the mortality
rate to 2 to 8 percent.
 PE Prognosis
Poor Prognosis:
• Elevated Brain Natriuretic Peptide
(BNP)
• Right Ventricular dysfunction
• Hypotension
• RV thrombus
• Elevated Troponin I
 PE Pathophysiology
• 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.
 PE Pathophysiology
• Iliofemoral veins are the source of most
clinically recognized PE.
• 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.
 PE Pathophysiology
• 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.
 PE Pathophysiology
• 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
cases.
 PE Pathophysiology
• Impaired gas exchange due to PE
cannot be explained solely on the basis
of mechanical obstruction of the
vascular bed and alterations in the
ventilation to perfusion ratio.
• Gas exchange abnormalities are also
related to the release of inflammatory
mediators, resulting in surfactant
dysfunction, atelectasis, and functional
intrapulmonary shunting.
 PE Risk Factors
• PE is a common complication of
deep vein thrombosis (DVT),
occurring in more than 50 percent
of cases with phlebographically
confirmed DVT.
• This suggests that factors that
promote the development of DVT
also increase the risk for PE.
 PE Additional Risks Factors in
Women
• Obesity (BMI ≥29 kg/m2)
• Heavy cigarette smoking (>25
cigarettes per day)
• Hypertension
 PE Symptoms
• Specific symptoms and signs are not
helpful diagnostically because their
frequency is similar among patients with
and without PE.
• 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:
 PE Symptoms
• Dyspnea at rest or with exertion (73
percent). The onset of dyspnea was usually
within seconds (46 percent) or minutes (26
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),
• Wheezing (21 percent)
 PE Signs
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),
• Jugular venous distension (14 percent)
 PE DVT Symptoms
• 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.
 PIOPED II
• Clinical characteristics of patients with acute
pulmonary embolism: data from PIOPED II.
Stein PD; Beemath A; Matta F; Weg JG; Yusen
RD; Hales CA; Hull RD; Leeper KV Jr; Sostman
HD; Tapson VF; Buckley JD; Gottschalk A;
Goodman LR; Wakefied TW; Woodard PK. Am
J Med. 2007 Oct;120(10):871-9.
 PE Labs
Routine laboratory findings are
nonspecific.
• Leukocytosis
• An increased erythrocyte
sedimentation rate (ESR)
• Elevated serum LDH or AST
(SGOT)
• Normal serum bilirubin.
PE Arterial Blood Gases (ABG’s)
• Arterial blood gas (ABG)
measurements and pulse oximetry
have a limited role in diagnosing
PE.
• ABG’s usually reveal hypoxemia,
hypocapnia, and respiratory
alkalosis.
 PE ABG’s
• 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.
 PE Chest X-Ray
• Radiographic abnormalities are
common in patients with PE;
however, they are not helpful
diagnostically because they are
similarly common in patients
without PE.
 PE Ventilation/Perfusion V/Q
Scan
• 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.
• Additional testing is required in this
situation.
 PE Venous Ultrasound
• Lower extremity venous
ultrasound is sometimes
performed during the diagnostic
evaluation of PE.
• The rationale is that venous
thrombosis detected by ultrasound
is treated similar to confirmed PE.
 PE Venous Ultrasound
However, there are flaws to this approach:
• False positive venous ultrasound studies (3
percent in one report) will result in the
anticoagulation of some patients who do not
have DVT or PE, thus subjecting them to
unnecessary risk.
• Many patients with PE are likely to be missed.
• In one report, only 29 percent of patients with
PE (determined by V/Q scan or pulmonary
angiogram) had venous thrombosis detected
by compression ultrasound.
 PE D-dimer Sensitivity
• D-dimer levels are abnormal in
approximately 95 percent of all
patients with PE when measured
by ELISA, quantitative rapid
ELISA, or semi-quantitative rapid
ELISA.
 PE D-dimer Specificity
• D-dimer levels are normal in only 40 to
68 percent of patients without PE,
regardless of the assay used.
• This is a consequence of abnormal D-
dimer levels being common among
hospitalized patients, especially those
with malignancy or recent surgery.
• The specificity may decrease further
with increasing patient age.
 PE Spiral CT
• Due to its widespread availability, spiral
(helical) CT scanning with intravenous
contrast (i.e., CT pulmonary angiography
or CT-PA) is being used increasingly as a
diagnostic modality for patients with
suspected PE.
• One of the most commonly cited benefits
of CT-PA is the ability to detect alternative
pulmonary abnormalities that may explain
the patient's clinical presentation.
 PE Spiral CT
• 83 percent of patients with PE had a
positive CT-PA (i.e., sensitivity).
• Conversely, 96 percent of patients
without PE had a negative CT-PA (i.e.,
specificity).
• Addition of venous-phase imaging
improved the sensitivity (90 percent),
while maintaining a similar specificity
(95 percent).
 PE Spiral CT
• The likelihood of PE in patients with a
positive CT-PA and a high, intermediate,
or low clinical probability was 96, 92, and
58 percent, respectively (i.e., positive
predictive value).
• The likelihood that PE was absent in
patients with a negative CT-PA and a low,
intermediate, or high clinical probability
was 96, 89, and 60 percent, respectively
(i.e., negative predictive value).
 PE Echocardiography
• Only 30 to 40 percent of patients
with PE have echocardiographic
abnormalities suggestive of acute
PE.
 Case 1
• A 22 year old thin, female student on OCP’s
presents to your clinic with painless, right calf
swelling
• She has elevated her leg for 2 days due to a right
ankle sprain during a soccer game.
• No prior medical history, recent surgery, or weight
change.
• She does not smoke and drinks rarely
• On exam her right calf is 1.5 cm larger than the left
 Case 1
• She has 2-3 risk factors: (OCP, trauma, +/-
immobolization)
• Her Wells score gives her a moderate risk
for a DVT.
• A D-dimer test is done.
 Case1
• She has a positive quantitative ELISA.
• An imaging study is done.
 Case1
• Available imaging and
ancillary tests:
– Compression US – first
line test, high sens/spec
– Venography – gold
standard
– MRI – Lower quality
evidence only at
present
 Case 1
• Compression US negative
• Options include:
– Venography or MRI
– Serial compression US – single US done at 5-7
days reliably excludes calf-limited DVT
– Follow clinically for resolution of symptoms –
riskier, no data supporting safety of this option
 Case 1
• The patient elected to be followed clinically.
She returned to clinic 3 days later with
persistent swelling, but no new symptoms
• She was to return the following week, but
instead you are called to the ER 10 days
later after she presents with acute onset of
dyspnea and pleuritic chest pain.
 Case1
• Findings in the ER
– Alert white female, mildly anxious
– T 101, HR 105, RR 18
– R LE edema and redness
– Lungs clear to auscultation
– ABG – mild respiratory alkalosis
– CXR showing mild atelectasis
• D-dimer positive as before, troponin normal
 Case 1
• Helical CT – segmental embolus
• Therapy
– Enoxaparin 1mg/kg sq every 12 hours for 5 days
– Warfarin started day 1 at 5 mg a day
– CBC on day 3-5 and INR every day if inpatient
– May stop enoxaparin after 5 days if INR > 2.0
– Warfarin continued to keep INR at 2.5 (2.0-3.0 range)
for ? 3 months
 Case 1
• Anticoagulation same for DVT & PE
• Compression stockings prevent post-
phlebitic syndrome
• Thrombolysis - risk/benefit uncertain;
clinical outcomes generally not improved
• Vena cava filters - limited evidence and
modest benefit