6 Venous Thromboembolism
Assessment of a Venous Thromboembolic Event
Deep vein thrombosis (DVT) and pulmonary embolism (PE) comprise venous thromboembolism (VTE). Together, they comprise a serious
health problem as there are over 600,000 new cases of VTE in the United States, resulting in a prevalence of one to two per
1,000 individuals, with some studies suggesting that the incidence may even be double that.1,2 The European Union reports an incidence of VTE of over 760,000 cases a year, with more than 370,000 VTE-related deaths, and
one third were sudden deaths.3 It is estimated that about 10 to 25% of patients with acute PE die from sudden death prior to diagnosis and, thus, do not
receive therapy, resulting in approximately 60,000 Americans dying each year from complications associated with VTE4–6 Postmortem studies have identified that sudden death from PE is misdiagnosed in almost 80% of cases,7 exemplifying the poor ability we have to identify and prevent it. Of the more than 500,000 patients who survive at least
1 hour to have the opportunity to be diagnosed and treated, only 29% actually receive treatment and 92% of them survive, whereas
the untreated 71% have a mortality of 30%.8 These numbers are staggering when compared with the death rates of other common diseases. Altogether, death from VTE is five
times more common than deaths from breast cancer, AIDS, and motor vehicle crashes combined.
The long-term complications of nonfatal DVT are morbid, including one third suffering postthrombotic syndrome (PTS) and another
30% having a recurrent VTE within 10 years of the first.2,9 Finally, in patients with cancer, VTE-related complications are the second leading cause of death; they increase the mortality
associated with increased bleeding complications and the use of health care resources.10–12
Patients with PTS may suffer poor quality of life as a result of chronic limb symptoms.13,14 PTS occurs in up to 30% of patients with DVT at 8-year follow-up, varying in severity from edema to venous claudication and
ulcers.15,16 Risks for PTS include recurrent DVT, a proximal (iliofemoral) DVT, older age, a high body mass index, and female gender.15 Preventing recurrent DVT is a primary means to decrease PTS. Most of the time, therapy for PTS is palliative, but at times,
patients with PTS require (or request) lower extremity amputations because of chronic, unrelenting pain and ulceration. A
12-year review of a Nationwide Inpatient Sample database sampling all hospitalized patients with chronic venous disease found
that 1.2% of patients underwent an amputation.13 This number may be higher at tertiary referral centers, which have a large number of complex venous patients.
Considering that PE and PTS are often preceded by DVT, there is an impetus for prevention, early detection, and aggressive
treatment of DVT prior to the presentation of these complications, all while providing appropriate acute management and evaluating
the response to treatment. This all begins with a careful history and physical examination.
The importance of obtaining a good history of present illness and review of systems in patients is critical in the decision
tree for the diagnosis and management of patients with acute VTE as subtle clinical findings may dramatically change the treatment
plan and are not driven by imaging or laboratory tests alone. For example, a patient with only shortness of breath or tachycardia
as a symptom or sign of PE may require a D-dimer prior to receiving any further treatment or imaging, whereas one with tachycardia
and leg swelling may benefit from anticoagulation prior to imaging (without needing a D-dimer) because of a higher likelihood
If a patient presents with a VTE, one must distinguish between those patients who have a temporary risk factor (such as surgery
or bed rest) and those who have a lifelong secondary condition, inherited disease, or undefined state that predisposes to
thrombosis and may benefit from prolonged anticoagulation after the VTE [see Table 1]. This distinction helps determine the long-term treatment and risk of future VTE.
In addition to advancing age, acquired VTE risk factors that are considered lifelong to the patient include a history of previous
VTE, active cancer (may be reversible in some cases), extremity paresis or paralysis, medical disorders causing prolonged
bed rest, and congenital or autoimmune thrombophilia. Temporary or provoked VTE risk factors include pregnancy, oral contraceptive
or hormone therapy, surgery and trauma, central venous catheters, and bed rest or other states of prolonged immobility.
Rudolf Virchow first stated in 1859 that clots in the pulmonary artery originated from the venous circulation and coined the
term “embolus.” He also described the three components of hypercoagulability that are now referred to as a triad that bears
his name: hypercoagulability, stasis, and injury to the vessel wall.18 These factors are still relevant today.
“Thrombophilia” is defined by the World Health Organization (WHO) as “a tendency towards thrombosis.”19 Thrombophilia, whether acquired or inherited, plays a direct role in about 50% of all VTEs. Most commonly, surgeons evaluate
patients for these risks preoperatively. Aggressive screening for VTE risk to provide appropriate prophylaxis or treatment
can best be obtained by interviewing the patient. These risks can be determined via group consensus guidelines such as those
of the American College of Chest Physicians (ACCP)20 or via the use of an individualized risk assessment scoring such as the modified Caprini score.21 The ACCP guidelines account for most risk scenarios by taking into account patient cohorts (e.g., all medical patients, those
undergoing hip replacement, patients with cancer, etc.). However, individual patients may overlap into several simultaneous
categories. Alternatively, individual risk assessment can be performed by directed intake sheet [see Figure 1]. This allows risk factor summation and suggests appropriate prophylaxis choices. The questionnaire collects information
from the patient’s personal (age) and medical history (e.g., family history of VTE, personal history of DVT) and takes into
consideration what type of procedure is to be done and the intended mobility status. This system has recently been retrospectively
Age alone confers an acquired thrombophilic state. Older patients tend to accumulate risk factors such as infections, surgery,
and cancer, each of which increases the likelihood of having thrombotic complications. Patients over 50 years of age also
have higher concentrations of antiphospholipid antibodies of unknown significance.22 The older the patient is who suffers a VTE, the lower the likelihood that the VTE was attributable to an inherited etiology
and, conversely, the greater the likelihood that it was attributable to an acquired condition.23 Older patients also have a higher risk of developing limb complications such as PTS15 as well as PE. Experimental animal data also suggest that age may lead to a higher concentration of P-selectin and impaired
fibrinolysis, which may contribute to age-related thrombophilia.24
The clinical constellation of asymptomatic cancer and lower extremity deep vein thrombosis (LEDVT) was first described in
1865 by Armand Trousseau,25 and this syndrome bears his name. The 19th century was also marked by the suggestion by Theodor Billroth that cancer used
clot as a mechanism to spread.26
Since then, a search for the etiologic factor involved in cancer-related thrombophilia has only been partially fruitful. A
“cancer procoagulant” factor was found in 1985 exclusively in amniochorial tissue and associated with multiple malignancies.27 It is a cysteine protease that specifically activates coagulation factor X. However, even after more than 25 years since
this discovery, it has been purified only from several malignant tissue cultures, and no gene has been identified.28
Of all types of malignancies, mucin-producing tumors such as adenocarcinomas, small cell lung cancers, gastrointestinal cancer
(such as the gastric cancer that led to Trousseau’s own DVT),29 and ovarian cancer are most likely associated with VTE.30 This notwithstanding, any malignancy increases the risk of VTE. Additional risk factors linked to patients with malignancies
are those related to therapy, such as central venous catheters, chemotherapy, and surgical procedures, all of which are independent
risk factors for VTE.31 An additional risk factor found in some cancer patients is an elevated (greater than 75th percentile) soluble P-selectin
concentration. It increases the cumulative DVT probability from 3.7 to 11.9% in multiple types of cancer.32 Whether mucin-producing cancers have increased P-selectin as the mechanism of thrombosis is under investigation.33
The WHO defines an inherited thrombophilia as “the presence of an inherited factor that by itself predisposes towards thrombosis
but due to the episodic nature of thrombosis, requires interaction with other components...before onset of the clinical disorder.”19 To evaluate patients with suspected primary thrombophilia, an international consensus was formed to standardize who needs
advanced testing. Indications for laboratory investigation of secondary thrombophilia are listed in Table 2, and venous thromboembolic risk according to hypercoagulable state are listed in Table 3.34,35
In 1994, the Leiden Institute discovered the point mutation in factor V that explains the most common inheritable thrombophilia.
This “factor V Leiden mutation” accounts for up to 25% of secondary thrombophilias.36 It occurs in 6 to 9% of whites and in up to 50% of families with a history of DVT.23,37 The G20210A mutation of the prothrombin (coagulation factor II) gene is another common etiology of thrombophilia that is
associated with DVT.36 Impaired fibrinolysis is a hypercoagulable state associated with 4G/5G polymorphisms of the plasminogen activator inhibitor–1
(PAI-1) gene. These patients have a threefold increased risk of DVT higher than the general population.38 As many as one third of non–catheter-related upper extremity deep vein thrombosis (UEDVT) may be due to the above-mentioned
Other notable inheritable syndromes include deficiencies of the natural anticoagulants, including antithrombin III and proteins
C and S.40,41 These tend to be more aggressive thrombophilias, with presentation in younger patients. Obtaining a positive screen for these
entities directs the long-term anticoagulation strategy for and future risk of VTE.
The majority of these factors are encountered in rheumatologic disorders. The disease most commonly associated with both arterial
and VTE is antiphospholipid syndrome. For decades, clinicians noted that patients with systemic lupus erythematosus (SLE)
would present with spontaneous clotting yet paradoxically have prolonged activated partial thromboplastin times (aPTTs).42 This is now known to be attributable to antibodies against the negatively charged phospholipids that interfere with the aPTT
assay itself. These antibodies are not specific to lupus as they may be independent (true antiphospholipid antibody syndrome
[APS]) or associated with other rheumatologic diseases, such as rheumatoid arthritis, systemic sclerosis, Sjögren syndrome,
and systemic vasculitis, among others. The most common antibodies identified are antiphosphatidylserine (lupus anticoagulant),
anticardiolipin, anti–β2-GPI, and sometimes antiprothrombin.43,44 There is a high IgM anticardiolipin antibody level in females when compared with males45 and an increased incidence of PE among APS patients. The exact mechanism for thrombophilia in APS is unknown,46 but it is not simply attributable to antibody- or complement-mediated activation of platelets.47 This is highlighted by the fact that clinically silent antiphospholipid antibodies may be found in as much as 2% of the population
(age related) and that although 30 to 40% of patients with SLE have antiphospholipid antibodies, only 10% will manifest with
Another rheumatologic disorder that confers an increased risk of arterial and venous thrombosis (particularly in the cerebral
sinus and lower extremities) is Behçet syndrome. This presents most commonly in patients from the “old silk road” (between China and the Mediterranean Sea) and
has yet to have a clear mechanism elucidated.49,50
Stasis is often considered a risk factor for VTE because of sluggish venous flow seen in a spectrum of scenarios ranging from
being seated on a transoceanic flight to a paralyzed trauma patient. Although this alone is an inconsistent risk for VTE,
even sitting in a chair for 6 to 8 hours may be what unmasks other, more prevalent VTE risk factors by increasing the regional
procoagulant factors in the region of stasis.51 A meta-analysis of medical patients suggests that the risk of VTE in immobilized patients is about twice that of ambulatory
The risk of VTE in those individuals with low or moderate risk after a flight lasting more than 4 hours has been studied and
is thought to be 1% or less and 4 to 6% in those who are high risk, presumably from prolonged immobilization.53,54 Although uncommon, the association of VTE with air travel has been linked to the distance traveled. The lowest risk occurs
after flights less than 3,000 miles (0.01 cases per million), and the highest occurs after flights greater than 6,000 miles
(4.6 cases per million).55 Given that these numbers are very small and that there are no control groups, consensus guidelines only recommend frequent
ambulation and compression stockings during long flights and reserve pharmacologic prophylaxis for patients with other major
risk factors for VTE.56 Most studies evaluating compression stockings to improve edema after long flights show a benefit, but their role in preventing
significant (DVT and PE) VTE depends more on the patient’s risk factors than on the length of the flight. It has not been
shown that stockings diminish the risk of DVT after prolonged air travel in patients who are low risk, regardless of the length
of the flight. Conversely, compression stockings likely reduce the risk of DVT after flights that last more than 8 hours in
all patients who are otherwise at high risk for VTE.54–59 Patients who are at moderate risk for DVT and travel more than 11 hours also may benefit from stockings with compression
gradients of 20 to 30 mm Hg, whereas no DVT has been demonstrated in this patient population after flights that last less
All patients undergoing surgical procedures have an increased risk of thrombosis, with an incidence ranging from 15 to 40%
and an odds ratio of more than 10 compared with controls.60 This may be attributable to accelerated production of procoagulant and inflammatory cytokines that activate platelets, inflammatory
cells, and endothelial cells in addition to postoperative inactivity, which increases blood stasis. Although controversial,
the incidence may also be attributable to reduced capacity for fibrinolysis during the perioperative period, associated with
increased PAI-1 activity.61,62 Procedures that require prolonged immobility in the postoperative period (such as hip replacements and spine procedures)
have the highest risk of DVT (historical prevalence 40 to 60%). Interestingly, decreased concentrations of fibrinolytic enzymes
have been documented in patients undergoing orthopedic procedures (compared with general surgical patients) and may partially
explain the greater thrombosis risk in these patients.63
Although preoperative and operative risk factors are important to predict VTE, the interventions and medical complications
associated with the patient’s postoperative course also impact the incidence of symptomatic VTE. A cohort study involving
over 76,000 patients having surgery in the Veterans Affairs system over a 5-year period found that the strongest predictors
of postoperative VTE were myocardial infarction, blood transfusion (> 4 units), pneumonia, and urinary tract infections.64 This suggests that postoperative systemic inflammatory conditions may substantially contribute to the thrombophilic state.
However, the exact mechanism(s) are unknown.
Major trauma patients are also known to be at high risk for VTE (historical prevalence of 40 to 80%),20 and DVT may occur in up to one third of patients (mostly in the calf of the leg) with a moderate to severe brain injury,
especially when associated with extremity injuries.65,66 For these reasons, prophylaxis with sequential compression devices (SCDs) and eventually heparin or low-molecular-weight
heparin (LMWH) when the bleeding risk is deemed safe are strongly encouraged (see below).
Macroscopically, vessel trauma and foreign bodies placed within veins damage the endothelium and will locally accumulate platelet
and coagulation factors. These conditions alone will usually not lead to vessel thrombosis, but when combined with other prothrombotic
factors, such as tissue factor, von Willebrand factor, and fibronectin, the likelihood of DVT increases.67 The conversion from local clot to occlusive thrombus is likely dependent on the time of exposure to the etiologic factor.
As such, central venous catheters (including peripherally inserted catheters) have a relatively high rate of thrombosis. Central
venous catheters account for two thirds to three quarters of UEDVT and are the strongest independent predictor of UEDVT (7.3-fold
Clinical Presentation of VTE
The most common presentation of DVT is limb swelling, calf pain, and discrepant circumference. However, the manifestations
of DVT or PE may be subtle and subclinical in many cases. It has been found that over 50% of patients with a DVT may have
an unrecognized PE (based on imaging testing)70 and that over 70% of patients with PE have an undiagnosed LEDVT.18
To aid in the appropriate management of PE, Wells and colleagues published clinical criteria that accurately stratify a patient
as low, moderate, or high risk and determine who needs further imaging to evaluate for PE.71 Their 2001 criteria for PE include hemoptysis, malignancy (patients with cancer who are receiving treatment or for whom treatment
has been stopped in the previous 6 months or those receiving palliative care), a history of DVT or PE, tachycardia, and no
other likely diagnosis. Additional criteria include immobilization for more than 3 consecutive days or surgery less than 30
days from presentation and clinical signs and symptoms of DVT (objectively measured calf swelling and pain with palpation
in the deep venous system). Wells and colleagues determined that in cases of low or moderate risk with a normal D-dimer (a
serum marker of fibrinolysis), no further imaging was necessary. However, if the D-dimer was positive, then a ventilation-perfusion
(V/Q) scan or angiogram was used to confirm the clinical suspicion. In patients with chest symptoms suspicious for PE, the
patient should be evaluated for these criteria to determine the need to pursue further imaging or laboratory studies. Patients
found to be at intermediate risk or high risk for PE should also be heparinized prior to obtaining imaging.72
The first Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study found that of the more than 250 patients
with angiographically demonstrated PE, only 11% had physical examinations consistent with DVT.73 Hemoptysis and pleuritic pain may be present in only about 40% of all patients with PE.74 Like DVT, patients with clinical manifestations of PE will likely only have nonspecific clinical findings. The most common
findings include dyspnea (84%), pleuritic pain (74%), apprehension (63%), and cough (50%). Of these clinically positive patients
with PE, dyspnea or tachypnea occurred in 96%, whereas 99% of them demonstrated dyspnea, tachypnea, or DVT.75 As in other diseases that are shared by the young and old, PIOPED II revealed that dyspnea or tachypnea was less commonly
reported in elderly patients.74
Rarely, massive iliofemoral DVT may cause phlegmasia alba dolens (swollen white/milk leg), a clinical scenario when arterial
inflow becomes obstructed as a result of extreme venous hypertension.25 Phlegmasia cerulea dolens (swollen blue leg) occurs from severe venous hypertension that occludes the capillaries and may
result in venous gangrene. The legs become red or purpuric, and the toes may become cyanotic and often is accompanied by blistering
of the skin [see Figure 2]. Venous gangrene is always preceded by phlegmasia cerulea dolens, and is often associated with an underlying malignancy.
The most common physical findings associated with LEDVT are edema, calf swelling, and tenderness, but these are not specific
to DVT. Homan sign (calf pain at dorsiflexion of the foot) and pain on manual compression of the calf muscle against the tibia
(Olow sign) are uncommon signs but are suggestive of calf DVT. The extremity may also be warm and ruborous with brisk capillary
refill, and care must be taken not to misdiagnose LEDVT for cellulitis. Although the lower leg is the most common site for
DVT, thigh pain and arm pain may also be noted in cases of iliofemoral and UEDVT, respectively.
Although physical examination alone is accurate in less than one third of cases,76 it is critical to determine the next step in the clinical investigation or treatment, particularly in the case of PE,77 and limb threat, which may mandate urgent therapies (see below). One must remember that unless there is vena cava thrombosis,
the clinical findings of DVT are rarely bilateral. This diagnostic rule assists in eliminating other systemic causes of lower
extremity edema, such as renal failure or congestive heart failure, which may manifest with edema. Other illnesses that may
mimic unilateral leg DVT include popliteal (Baker) cysts, trauma, cellulitis, popliteal aneurysm thrombosis, lymphedema, and
Patients with phlegmasia syndromes will have dramatic swelling associated with tight, plethoric extremities that may be ruborous
or pale. A careful evaluation of the motor function of the extremity is necessary to determine which patient has immediate
limb threat and requires urgent intervention to resolve the venous hypertension or open the compartment [see in Indications for Immediate Intervention (Limb or Life Threat), below].
Superficial venous thrombosis may often manifest in the setting of a vessel cannulation. Superficial thrombophlebitis is most
often accompanied by pain, an inflamed palpable cord, or both along the axis of the affected vein. Sometimes this may also
be accompanied by extremity edema and, if infected, may have purulent discharge at the catheter site.78
D-dimer is most useful for ruling out a VTE in a low-risk patient. If negative, there is almost no risk for VTE, and no further
testing is required. This clinical strategy has been adopted by both the American and European consensus groups as the appropriate
workup for a VTE.56,60 However, D-dimer is not useful for those patients with a high pretest probability of a VTE. We now know that in patients
with a high clinical suspicion of VTE, almost 10% may have a false negative D-dimer assay with a VTE, although in those with
a low suspicion, it will be accurate nearly 100% of the time. Thus, in a high-risk patient, a D-dimer will not safely rule
out a VTE; thus, there is no reason to obtain such a level in a high-risk or even a moderate-risk patient.79 Furthermore, patients who have undergone surgery or trauma may have an elevated D-dimer from postoperative blood that is
being lysed, and this finding may be elevated for over 2 weeks.80 Thus, D-dimer has less utility in the postoperative period, and reliance on imaging such as computed tomographic angiography
(CTA) for PE is important.
Whenever possible, blood screening for patients suspected of thrombophilia should use samples obtained prior to anticoagulation
to obtain a baseline partial thromboplastin time, prothrombin time, platelet count, antithrombin, and proteins C and S levels,
although with significant thrombosis, these coagulation proteins may be consumed into the thrombus, leading to falsely low
levels. Anticoagulation will also change the above-mentioned values. However, accurate results can help predict the etiology
of the hypercoagulable state. For example, a prolonged aPTT may be attributable to antiphospholipid antibody syndrome, whereas
a low protein C may be attributable to genetic protein C deficiency. The remaining genetic or antibody tests obtained during
a thrombophilia evaluation, such as factor V Leiden mutation, factor II G20210A mutation, anticardiolipin, anti–β2-GPI, and fasting homocysteine, will not be altered by anticoagulation and can be obtained at any time in the patient’s course.
When used in symptomatic patients, compression duplex ultrasonography (CDU) alone has a sensitivity to detect proximal DVT
and calf DVT of 96% and 80%, respectively. In asymptomatic patients, the sensitivity is significantly lower (76% for proximal
calf DVT and 11% for isolated calf vein thrombosis).81 Thus, CDU is the initial screening and diagnostic test of choice in patients with a moderate to high suspicion for DVT or
is the second test to be done if a positive D-dimer assay is found when evaluating a low-risk patient for a DVT.
The diagnosis of PE may be further studied with a radionuclide V/Q scan, pulmonary CTA, or pulmonary arteriography. Vena cava
or extremity venography is rarely indicated except when combined with a planned catheter-directed fibrinolysis procedure (e.g.,
May-Thurner or Paget-Schroetter syndrome).
Although V/Q scans do not require radiation or use nephrotoxic contrast agents, they provide a definitive diagnosis in less
than half of cases, with a sensitivity of only 41%.73Anywhere from 30 to 70% of V/Q scans are interpreted (often erroneously) as “indeterminate,” and the management of these patients
is unclear, especially as 30 to 40% of these patients may have a PE and are not treated appropriately.82 This modality has fallen out of favor except where a CTA cannot be obtained and the pulmonary function portion of the test
is predicted to be normal. When a patient has other pathologies that alter the ventilatory (such as chronic obstructive pulmonary
disease or pneumonia) or perfusion portions (previous infarcts, previous lung resections, or old infarcts) of the test, V/Q
imaging is not useful for detecting acute PE.
A prospective multicenter trial evaluating multidetector CTA alone versus CTA combined with venous phase computed tomography
(CT) of the pelvic and thigh veins for the diagnosis of acute PE was conducted in the PIOPED II study.74,83 It revealed that combining pulmonary CTA with CT venography (in the same scan) was more useful in managing suspected PE and
DVT than by pulmonary CTA alone. The combination of pulmonary CTA and CT venography for PE yielded a sensitivity and specificity
of 90% and 95%, respectively. If the clinical findings correlated with the CT findings, then the positive predictive value
is over 92% in all scenarios. Another benefit of the use of CT, even though it requires the infusion of intravenous contrast
dye and radiation,84 is that although it is positive in less than one third of patients who undergo CTA for PE, an alternative diagnosis may be
found in more than 70% of those patients.
Of the available imaging modalities, pulmonary arteriography is the most invasive and exposes the patient to potentially nephrotoxic
contrast dye. Although historically this was considered the diagnostic test of choice, the use of high-resolution CTA is now
the standard for the aforementioned reasons. Angiography is more commonly used when catheter-directed thrombus removal is
being contemplated (see below).
Without prophylaxis, surgical procedures may have a VTE prevalence of up to 80%.20 Historically, trials comparing no perioperative VTE prophylaxis with prophylaxis methods ranging from stockings and SCDs
or any form of anticoagulation showed that each prophylactic modality could decrease the risk of VTE at least two- to threefold.85–87 For this reason, every patient undergoing surgery should have some form of prophylaxis unless it is a minor or ambulatory
procedure and the patient has no other VTE risk factor other than the procedure (see below).56 There is no evidence to support the use of inferior vena cava (IVC) filters for perioperative or peritrauma PE prophylaxis
without the diagnosis of DVT [see Vena Cava Filters,below].
As previously stated, one way to determine prophylaxis recommendations is the ACCP consensus guidelines.20 Whether based on a category or risk score, most at-risk patients who undergo major surgical procedures or suffer significant
trauma should receive prophylaxis with an anticoagulant unless they have a high bleeding risk; in these cases, SCDs are recommended
until the bleeding risk subsides. In high-risk VTE cases such as in spine injury or hip replacement, stronger pharmacologic
agents (LMWH, pentasaccharides, or warfarin) are recommended for prophylaxis, whereas unfractionated heparin (UFH), SCDs,
and aspirin alone are not effective prophylaxis [see Table 4]. In surgical procedures where the bleeding risk outweighs the benefit of an anticoagulant, such as certain neurologic and
vascular procedures, mechanical prophylaxis usually suffices. These include graduated compression stockings and SCDs, which
are comparable to low-dose heparin in patients without other risk factors.88 The caveat is that these devices need to be on the patient’s limbs and working, requiring surveillance for compliance.
Barring a medical contraindication, full-dose anticoagulation should be started in cases of high clinical suspicion for PE
until it is refuted as the cause.56 If PE is diagnosed, then anticoagulation should be continued with either continuous UFH titrated to an aPTT of 60 to 80 seconds,
weight–based, full-dose LMWH, or fondaparinux according to both the American (ACCP) and European (European Society of Cardiology)
The management of PE is then determined by the clinical severity, highlighting the importance of a good medical history and
physical examination.77 Massive, unstable PE consists of shock and/or hypotension (systolic blood pressure < 90 mm Hg or drop of 40 mm Hg for > 15
minutes without other cause), usually associated with severe shortness of breath or respiratory insufficiency. Nonmassive
PE should be evaluated for echocardiographic signs of right ventricular hypokinesis (“submassive” PE), which may still require
thromboreduction of some sort, whereas lack of right heart strain allows for systemic anticoagulation alone. In addition to
emergent echocardiography, serum brain naturetic peptide levels and serum troponins may aid in stratifying the severity of
In the case of clinically unstable PE or submassive PE with significant right heart strain, thrombolytics are the treatment
of choice (barring contraindication to them). They can be administered systemically if the patient is too unstable for transfer
or if the technical requirements are not available for catheter-directed administration. Systemically, tissue plasminogen
activator 10 mg bolus followed by a continued infusion of the remaining 90 mg over 2 hours is administered. This may acutely
avoid cardiogenic shock and death or, later, the development of chronic thromboembolic pulmonary hypertension.89
An evolving treatment option for hemodynamically significant PE is endovascular catheter-directed infusion of lytics into
the affected pulmonary vessel or mechanical thrombus reduction. A combination of transjugular, catheter-directed pulmonary
embolectomy and thrombofragmentation with fibrinolytics is performed. This technique has been successful in three quarters
of cases, with a mortality of 25%.90 The technology involved in these techniques is still being developed. As a result of the scarcity of both patients with this
form of PE and physicians experienced in catheter-directed treatments for PE, the ideal technique is still unclear.91 In patients with cardiopulmonary instability who either cannot wait for pharmacologic thrombolysis to work or have a contraindication
to thrombolytics, open thrombectomy is the only other option. The mortality is high, but in centers with experience, the outcomes
are improved over no treatment.
After parenteral anticoagulation has been established, anticoagulation is continued with a vitamin K antagonist (VKA) for
3 to 6 months if the PE was attributable to an isolated or acquired etiology or continued for life if the PE was attributable
to a permanent or recurrent etiology.56
As described above, phlegmasia cerulea dolens and phlegmasia alba dolens of the limbs have amputation rates of 20 to 50% (prior
to the advent of fibrinolytic therapies) and PE rates of 12 to 40%. Phlegmasia syndromes have a high mortality rate that in
addition to the acute, extensive DVT is also likely attributable to the comorbidities that tend to accompany them, such as
advanced malignancy and trauma.92 Phlegmasia syndromes that are associated with acute iliofemoral vein thrombosis have been successfully treated by catheter-directed
fibrinolysis. There is no specific endovascular technique shown to be superior to others, but in small series, endovascular
techniques show great promise for limb salvage and is the preferred management strategy if the patient still has good motor
function and no contraindication to lytics.93,94 If the patient is not a candidate for fibrinolysis, then open surgical venous thrombectomy and creation of an arteriovenous
fistula are necessary to obtain rapid venous decompression and decreased risk of PTS.95,96
If the phlegmasia syndrome appears secondary to extensive, microvascular venous thrombosis (and not iliofemoral vein thrombosis),
then it is unlikely to benefit from thrombolytic procedures; limb salvage may thus be possible only with fasciotomies. Another
scenario potentially requiring fasciotomies for limb salvage occurs if there is evidence of advanced compartment syndrome
(motor impairment), although the morbidity of this in the setting of an acutely swollen leg is quite high.
Primary thrombosis of the axillary-subclavian veins is usually found in young athletes who perform sports with repetitive
motion (e.g., baseball, volleyball, swimming) and is known as effort thrombosis or Paget-Schroetter syndrome. It is attributable
to hypertrophy and/or a lateral insertion of the subclavius muscle, which compresses the subclavian vein and promotes thrombosis.
This syndrome was historically treated with anticoagulation alone with a high rate of pain and swelling, but in the last decade,
the treatment has evolved, and patients do better with multimodality treatment.97
Current treatment includes early anticoagulation and endovascular thrombolysis and recanalization of the axillary-subclavian
vein with balloon venoplasty of the narrowed segment. To return patency to the subclavian vein, thrombolysis may require a
several-day infusion of plasminogen activators and/or the use of endovascular devices to fragment clots and aid thrombolysis.
If the subclavian vein can be recannulated, then this treatment is followed by removal of the ipsilateral first rib to decompress
the thoracic outlet to avoid rethrombosis. The timing for surgical removal of the rib varies by practitioners; some perform
it during the same hospitalization, whereas others remove it a few weeks later. Attempts with angioplasty or stenting without
prior surgical decompression will invariably fail. Neither can overcome the extrinsic pressure created by the musculoskeletal
compression of the vein, and the constant motion of the subclavian vessels at this site will lead to stent fracture.98,99 If the vein cannot be opened, then the patient can only be anticoagulated and must rely on venous collaterals.
Iliac vein compression syndrome and secondary thrombosis (May-Thurner syndrome) occur when there is an obstruction or thrombosis
of the lower left extremity venous outflow as a result of compression by the overlying right iliac artery. They most commonly
present spontaneously in the left iliac vein and in young females who may or may not have additional risk factors for DVT,
such as factor V Leiden or the use of oral contraceptives.100,101 They rarely affect the right iliac vein and vena cava but can occur in cases with a high iliac artery bifurcation or left-sided
IVC.102 They can be successfully treated with endovascular venoplasty and stenting [see Figure 3] because unlike Paget-Schroetter syndrome, the extrinsic compression to the vein is not attributable to a firm, muscular
Historically, iliofemoral DVT was treated exclusively with anticoagulation or open thrombectomy with subsequent anticoagulation.96 However, many small series using catheter-directed thrombolysis and mechanical thrombolysis to treat iliofemoral DVT are
rapidly demonstrating less PTS than with anticoagulation alone.103,104 There is a growing consensus that in addition to anticoagulation, primary iliofemoral thrombosis and May-Thurner syndrome
should be treated with catheter-directed thrombolysis and placement of a closed-cell stent in the compressed vein (or residual
thrombus) to diminish PTS and maintain patency.56,105 The placement of stents and evaluation of residual stenosis is often guided by the use of intravascular ultrasound probes
in addition to venograms to ensure that the confluence of the vena cava is not compromised.106 The randomized, multicenter Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT)
trial (ClinicalTrials.gov identifier: NCT00790335)107 and the European Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis (CaVenT) trial (ClinicalTrials.gov
identifier: NCT00251771)108 are both enrolling patients to evaluate the outcomes of anticoagulation alone versus the use of pharmacomechanical means
for thrombus removal in the iliofemoral segment.
In addition to the use of plasminogen activator infusions into the thrombus, there are many different types of endovascular
devices designed to accelerate the resolution of vessel thrombosis. They range from physically breaking up the clot with a
spinning cage to catheters that spray fluid (saline, heparin, or tissue plasminogen activator) from multiple holes at a high
pressure to fragment and aspirate the thrombus. None have been compared in a head-to-head randomized study and collectively
have variable published effects on the reduction of thrombolysis infusion and final vessel patency. However, small studies
seem to show that pharmacomechanical lysis may minimize the amount of thrombolytic administered and the total treatment time
required to complete thrombolysis.109–111
If the thrombus extends below the inguinal ligament, then open thrombectomy and an arteriovenous fistula may be required to
improve the venous inflow and potentially decrease recurrent thrombosis, as well as the sequelae of PTS.112 All cases are subsequently managed by anticoagulation with a VKA.56
Avoiding the progression and recurrence of DVT is paramount to decrease both the incidence of PE and the occurrence of PTS.
The risk of the latter is dramatically increased in the setting of recurrent DVT (hazard ratio 6.4).16 To avoid this progression, all treatment guidelines recommend that patients with uncomplicated DVT be initially anticoagulated
using a parenteral drug (UFH, LMWH, fondaparinux, or hirudin derivative) followed by an oral VKA lasting at least 3 months.56,60 The VKA is titrated to achieve a target international normalized ratio (INR) between 2.0 and 3.0, and, subsequently, the
parenteral drug is ceased.
Almost 90% of patients anticoagulated for only 3 months for VTE will not have a recurrence within 5 years, but because of
the morbidity associated with recurrences, much effort has been made to identify patients at risk for recurrences. It has
been found that those with an elevated D-dimer or continued scar tissue (from unresolved thrombosis) visualized on CDU seen
at the 3-month evaluation should continue their anticoagulation to lower their risk of recurrence.113,114 For example, if CDU reveals significant residual scar tissue, there is a hazard ratio of 2.4 for recurrent DVT; therefore,
these patients may benefit from continued anticoagulation until the risks associated with prolonged anticoagulation are deemed
by the clinician to be greater than the risks of recurrent DVT.113,115
In patients with DVT and cancer, continued treatment with LMWH is recommended as long as the cancer is active or for at least
3 months of therapy (whichever is longer). This is because the risk of DVT recurrence in these patients is up to 14%, and
there is a higher risk of prolonged thrombus resolution (only 23% at 1 year) even with long-term anticoagulation.16,30,116
Compression stockings should be worn immediately on starting therapy to decrease the risk of PTS and continued as long as
the patient has swelling, usually for at least 2 years.56 This measure is often forgotten and can significantly reduce the long-term risk of PTS.
Patients with certain inherited or antibody-mediated hypercoagulable states are at high risk for recurrence, and risk assessment
needs to be obtained to determine if they require lifelong anticoagulation.117 There is no indication for anticoagulation with a VKA to an INR over 3, regardless of the risk factor, even in cases of antiphospholipid
syndrome that have the highest risk of arterial and venous thrombotic syndromes, as found by both randomized controlled trials
and the ACCP guideline statement.56,118
General consensus for the management of UEDVT associated with catheter placement is to use anticoagulation, but some controversy
exists regarding whether to remove the offending catheter. The 8th ACCP guidelines state that if the catheter is functional,
then there is no need to remove it, and anticoagulation therapy is initiated alone as for LEDVT.56 A recent study found that when specifically looking at complete thrombus resolution in UEDVT, only removing the catheter
had a significant impact on complete thrombus resolution (52% versus 25%, odds ratio 3.25), whereas anticoagulation alone
did not have an impact on resolution (36% with anticoagulation versus 56% without any anticoagulation; p = .10).119 Of note, patients who had a catheter replaced had an increased risk of a new clot, thus highlighting the thrombophilic state
of patients with catheter-related DVT.
Generally, uncomplicated superficial vein thrombosis (particularly when associated with intravenous catheters) can be treated
with local warmth and oral or topical antiinflammatory agents to control symptoms.120 However, there has been growing concern over the rate of underappreciated extension into the deep venous system resulting
in PE. The incidence of PE and DVT has been reported as high as 25% with lower extremity superficial vein thrombosis.121 Thus, duplex ultrasonography is now recommended for cases of superficial vein thrombosis, and if propagation or encroachment
into the deep system is seen, then systemic anticoagulation for 3 months is recommended.56 Surgical excision of superficial vein thrombosis may be indicated if the patient has prolonged or incapacitating pain, if
there is no resolution of the acute clot after 3 months of treatment, or as an alternative to anticoagulation if propagation
into the deep system is identified.78,120
With the advent of great saphenous vein ablations using catheter-delivered energy (laser or radiofrequency thermal energy)
for chronic venous insufficiency, an increased number of thrombi have been identified at the saphenofemoral junction. Although
there is no consensus for the management of this problem, if clot propagation into the femoral vein is identified during the
initial procedure (thrombus “tail”), then we immediately start LMWH and treat for 1 week, although the evidence for the need
for this treatment is evolving. Most clots resolve in this short interval of time. However, if a clot continues to be seen
near or extending into the deep venous system, then standard DVT treatment guidelines may be followed or surgical thrombus
removal and ligation of the saphenous vein can be performed as an alternative (particularly if there is a contraindication
Local intravenous catheter-site infections may occur in up to 8% of venous accesses and 18% of arterial catheterizations.
Although most do not result in systemic infections, bacteremia can be detected in about one of every 400 intravenous catheterizations
and 4% of arterial ones.122 Localized catheter-site infections may progress to superficial suppurative thrombophlebitis. In these cases, excision or
open phlebectomy is indicated to drain all pus, remove the infected hematoma, and control the spread of the thrombosis and
infection, removing the entire involved vein. Prevention is best obtained by changing all intravenous sites every 48 to 72
IVC filters lower the risk of fatal PE in patients with a DVT who are unable to be anticoagulated or in those who have a recurrence
during therapeutic anticoagulation. However, IVC filters are placed in many patients because of the relative ease of the procedure,
but often with unfounded indications. A prospective study of over 5,400 patients with DVT in an American registry found that
14% (781) of them had an IVC filter implanted. The indication in one third of these was only “prophylaxis” and not treatment
failure.123 There is evidence that DVT prophylaxis is used in less than half of surgical patients, with a concomitant increase in the
placement of IVC filters that may not be indicated.124
IVC filters should be placed only in cases where there is a contraindication to anticoagulation or when there is VTE recurrence
in the setting of therapeutic anticoagulation. In most instances, IVC filters should not be used in patients without a DVT
or PE as a prophylactic measure alone, regardless of the DVT risk factors, including trauma, surgery, and even cancer.125 Although an example of an indication for a temporary IVC filter may be a trauma patient at high risk for bleeding (contraindication
for anticoagulation) with a concomitant DVT or PE, filters are commonly placed as a prophylactic measure (patients without
a DVT or PE) in patients undergoing bariatric surgery, after trauma, or with spinal cord injuries even though studies and
consensus statements recommend against it.20,56,60,126
Patients undergoing bariatric surgery have been undergoing a dramatic increase in the placement of prophylactic IVC filters
(from 7 to 55% of patients over the last 10 years).127 Using only pneumatic compression devices and early ambulation, the risk of DVT in laparoscopic Roux-en-Y gastric bypass is
only 0.3%.128 Studies using IVC filters for primary prophylaxis in bariatric surgery have demonstrated a 2% incidence of PE, in the setting
of a 2.5% incidence of IVC filter complications, which include hemopericardium and pneumothorax.129 The lack of methodologically sound studies and an overall low incidence of VTE (in patients who can usually ambulate and
receive all other forms of mechanical and pharmacologic prophylaxis) have led to an overall consensus by the ACCP and others
that filters not be used for primary VTE prophylaxis in this or any other surgical procedure.130
Deployment of a vena cava filter may be done via the common femoral or the internal jugular veins. Although femoral access
is generally used, preplacement imaging of the venous system is imperative to determine if the access route is without thrombus.
If clot is identified, then the filter should not be placed through this route to minimize embolization. If there is thrombus
in the IVC, then the filter must be placed above it via the internal jugular access. Venography is also done to ensure that
the patient has normal venous anatomy (he or she may require two filters if a duplicated vena cava is found), to identify
the location of both renal veins to choose the site for deployment, and to measure the diameter of the IVC (it must be less
than 30 cm for most filters to minimize their migration). Filters are generally positioned in the IVC with their fixation
prongs caudal to the renal veins.
There are two broad types of vena cava filters: permanent and removable. The longest follow-up for a single IVC filter is
the permanent, over-the-wire Greenfield filter, which, after more than 20 years, has a very low incidence of IVC thrombosis
(< 4%) and migration (only non–clinically significant in 8%)131 and has not increased the incidence of DVT.132 The randomized PREPIC trial compared the long-term outcomes of patients with DVT treated with four different permanent filters
and anticoagulation with the outcomes of patients treated with anticoagulation alone for 3 months. The authors found that
although at 8 years there was a significantly lower incidence of PE (6.2% versus 15.1%, p = .008) in those with IVC filters, no difference in mortality or PTS was found. However, an increased risk of DVT (35.7%
versus 27.5%, p = .04) was observed in the group receiving a permanent filter. Of note, almost half of the patients with filters registered
to have had a DVT also had filter thrombosis.133,134 Permanent filters are covered with endothelium and affix into the IVC wall after 2 to 3 weeks, so the risk of attempting
to completely remove them in the operating room may be very high.135 In general, we have found that if IVC filter prongs protruding from the vein wall cause symptoms or bleeding, then the metal
that is visible outside the IVC should only be trimmed flush with the vein (in addition to any other repair needed), and the
remaining filter should be left in place.
To treat patients with filters only during their acute thrombophilia, optional retrievable filters have become more popular
than permanent ones. The theoretical advantage of using retrievable filters for patients with temporary prothrombotic states
is often mitigated by poor long-term follow-up, and over 75% are never removed, even in the military experience,136,137 or may require extreme surgical techniques to remove them when complications arise.138 These include migration, IVC thrombosis (2 to 14%, especially in biconcave retrievable or bird nest filters),139 renal vein thrombosis, and erosion into bowel140 or aorta.141
There is no large randomized trial assessing the use of superior vena cava (SVC) filters for UEDVT. Almost two thirds of patients
with SVC filters will die of their underlying diseases, and not of PE, within 2 months of placement.142 SVC perforations from filters with migration may result in a high mortality secondary to tamponade.143 Once they are in place, it is imperative to adequately warn all practitioners that the SVC filter is there to avoid blind
central line placement with standard J wires that may dislodge the filter or entangle themselves in it.144 Therefore, the benefit of SVC filters is still unclear for patients with UEDVT, and they should be judiciously used for patients
whose mortality is high from other causes.
Financial Disclosures: None Reported
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* The authors and editors gratefully acknowledge the contributions of the previous authors, John T. Owings, MD, FACS, to the
development and writing of this chapter.
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