6 Venous Thromboembolism

Guillermo A. Escobar, MD, Thomas W. Wakefield, MD, FACS, and Peter K. Henke, MD, FACS*

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.

Clinical Evaluation


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 of PE.17

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.

Medical History


THROMBOPHILIC RISK FACTORS

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 validated.21

IRREVERSIBLE RISK FACTORS FOR VTE

Age

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

Malignancy

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

Inherited Thrombophilia

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 inheritable disorders.39

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.

ANTIBODY-MEDIATED AND RHEUMATOLOGIC RISK FACTORS

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 thrombosis.48


Figure 1 Modified Caprini Score Questionnaire

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

ACQUIRED RISK FACTORS FOR VTE

Immobilization

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 patients.52

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 than this.

Surgery and Trauma

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).

Intravenous Catheters

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 increase).68,69

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.


Figure 2 Phlegmasia Cerulea Dolens

Physical Examination

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 muscle strain.

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

Laboratory Evaluation

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.

Imaging


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).

Prophylaxis against Perioperative VTE

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.

Indications for Immediate Intervention (Limb or Life Threat)

PULMONARY EMBOLUS

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) guidelines.56,60

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 PE.

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

PHLEGMASIA CERULEA DOLENS AND PHLEGMASIA ALBA DOLENS

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.

Indications for Urgent Intervention

PRIMARY AXILLARY-SUBCLAVIAN VEIN DVT (EFFORT THROMBOSIS OR PAGET-SCHROETTER SYNDROME)

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.

ILIOFEMORAL DVT AND MAY-THURNER SYNDROME

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 structure.

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.


Figure 3 Lower Extremity Venogram

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

Management of Nonemergent VTE

UNCOMPLICATED LOWER AND UPPER EXTREMITY VTE AND FOLLOW-UP

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.

SUPERFICIAL VEIN THROMBOSIS AND SUPPURATIVE THROMBOPHLEBITIS

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 to anticoagulation).

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 hours.

VENA CAVA FILTERS

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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