Prevention and Treatment of Venous Thromboembolism

Epidemiology

Venous thromboembolism (VTE), whose principal clinical manifestations include deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common cause of morbidity and mortality. The annual incidence of VTE has been estimated to be 104 to 183 per 100,000 among whites of European enthnicity. In an analysis of the California Discharge dataset, White et al. noted that the incidence of VTE was higher among African Americans (138 per 100,000 [95% confidence interval : 132 to 145]) than among whites (103 per 100,000 [95% CI 101 to 105]), Hispanics (61 per 100,000 [95% CI 59 to 64]), and Asian/Pacific Islanders (29 per 100,000 [95% CI 27 to 32]). However, in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, Zakai et al. noted that rates of VTE among African Americans were significantly higher than whites only in the southeast United States.

Age has a profound influence on the incidence of VTE. VTE is rare among children younger than 15 years (annual incidence <5 per 100,000). During adulthood there is a gradual rise in incidence until age 60 years, after which rates increase dramatically. Among persons 80 years or older the estimated annual incidence is 450 to 600 per 100,000. The incidence of VTE among men and women is roughly similar. Some studies have noted a slightly higher incidence among women during their reproductive years, although other studies noted no difference. Among individuals age 60 or older, studies have noted higher rates for men whereas other noted an increased risk among women. The annual incidence of DVT is approximately twice the frequency of PE (45 to 117 per 100,000 vs. 29 to 78 per 100,000). Over the past 20 years, PE has seemingly increased in frequency relative to DVT, likely owing to improved imaging techniques.

Pathogenesis of Venous Thrombosis

Normal hemostasis is characterized by a fine balance between prothrombotic and antithrombotic forces in the blood. The prothrombotic potential of the blood is expressed primarily by platelets and coagulation proteins. The endothelium, which expresses tissue plasminogen activator (tPA), prostacyclin, tissue factor pathway inhibitor (TFPI), thrombomodulin, (TM) and endothelial protein C receptor (EPCR), counterbalances the prothrombotic activity of platelets and coagulation factors. Blood flow reduces the likelihood of concentration of activated coagulation factors and thus decreases blood clot formation.

This balance is disrupted by vascular injury, stasis, and/or inflammatory conditions. Vascular injury exposes subendothelial tissue factor (TF) and collagen, which promote activation of the coagulation cascade and platelet adherence and activation. Simultaneously, vascular injury reduces the local expression of tPA, TM, EPCR and TFPI tipping the balance toward clot formation. Vasoconstriction at the site of injury reduces local blood loss and increases stasis, resulting in increased concentration of activated coagulation proteins. Inflammation promotes thrombosis by increasing the expression of factor VIII and reducing the concentration of free protein S by inducing C4b-binding protein synthesis. In addition, inflammatory cytokines induce monocytes to express TF and neutrophils to release neutrophil extracellular traps (NETs), which promote thrombus formation.

Risk Factors for Venous Thromboembolism

The classic model of thrombus formation encapsulated by the Virchow triad of stasis, vessel wall injury, and hypercoagulability serves as a useful conceptual framework for identifying the prothrombotic elements responsible for individual episodes of VTE. Similar to cancer, VTE is thought to represent the end product of a multistep process during which there is an accumulation of individual risk factors of sufficient potency such that the thrombosis threshold is exceeded and pathologic clot formation occurs. In recent years an increasing number of acquired and congenital risk factors of varying potency have been identified that influence the risk of VTE ( Table 16.1 ). Commonly cited VTE risk factors include surgery, malignancy, immobilization, major trauma, hormonal therapy (i.e., estrogen-containing oral contraceptives or hormone replacement therapy), pregnancy/postpartum state, acute medical illness, thrombophilia and especially a history of prior VTE.

Surgery is a potent VTE risk factor that peaks at more than 110-fold the incidence in the general population within the first few weeks after surgery and remains substantially elevated for more than 12 weeks post procedure (see Chapter 34 ). In the Million Women study, the risk of VTE was still elevated 10 to 12 months post operation (relative risk [RR] 3.7 [95% CI 2.8 to 4.9]). Outpatient surgery is associated with a lower but still significant 9.6-fold (95% CI 8.0 to 11.5) risk of VTE within the first 6 weeks post surgery. The RR of VTE associated with outpatient surgery remains elevated for 7 to 12 weeks (RR 5.5 [95% CI 4.3 to 7.0]), 4 to 6 months (RR 3.7 [95% CI 3.0 to 4.5]), 7 to 9 months (RR 2.6 [95% CI 2.0 to 3.3]), and 10 to 12 months post operation (RR 2.6 [95% CI 2.0 to 3.4]). In the Million Women study, hip and knee replacement surgery (7.7 per 1000 persons-months), cancer surgery (4.4 per 1000 person-months), hip fracture surgery (3.8 per 1000 person-months), and vascular surgery (3.1 per 1000 person-months) were associated with a high risk of VTE.

In an analysis of the National Surgical Quality Improvement Project, Kim et al. found that the risk of VTE varies with the type and duration of the surgical procedure. Compared with surgical procedures of average duration, surgical procedures with the longest operative times were associated with 1.27-fold greater risk of VTE. In their analysis, cardiothoracic and neurosurgical procedures were associated with the greatest risk.

Cancer is associated with a fourfold to sevenfold increased risk of VTE that varies with the primary site, stage, and histology (see Chapter 23 ). Pancreatic, gastric, brain, lung, and hematologic malignancies are associated with the highest risks of VTE, whereas breast and prostate cancer are associated with lower risks. Stage 3 and 4 tumors are associated with a substantial higher risk of VTE than is stage 1 or 2 disease. High-grade tumors are associated with twice the risk of low-grade tumors. Risk of VTE also varies during the course of disease, being higher in the first few months after diagnosis followed by a gradual decline.

Cancer treatments also influence risk. Consistent with the data for surgical patients, the risk of VTE peaks in the first 2 months after breast cancer surgery and then declines. In breast cancer patients, chemotherapy was associated with a 10.8-fold increased risk of VTE during therapy, which declined to baseline 3 months after completion. Hormonal therapy was associated with a 2.4-fold increased risk of VTE during the first 3 months of therapy, which varied by agent. Tamoxifen was associated with a 5.5-fold increased risk, whereas aromatase inhibitors were not associated with an increased risk. The risk of VTE was particularly high when surgery was performed in the 2 months after chemotherapy. Immunomodulatory agents such as thalidomide have been associated with an increased risk of VTE in multiple myeloma patients, particularly when used in conjunction with high-dose dexamethasone (≥480 mg/month). In contrast, bortezomib, bevacizumab, and small molecular weight epidermal growth factor receptor antagonists have not been associated with increased risk. Supportive care agents such as erythropoiesis stimulatory agents (ESAs) increase the risk of VTE by 1.7-fold.

The risk of VTE in cancer patients synergizes with preexisting individual patient risk factors. Age 65 years or older (odds ratio [OR] 1.1), female sex (OR 1.1), and African American ethnicity (OR 1.2) have been associated with a slightly increased risk of VTE, whereas Asian patients have decreased risk (OR 0.74). Factor V Leiden heterozygosity is associated with a twofold higher risk of VTE. Comorbid conditions such as obesity (OR 4), infection (OR 1.8), renal disease (OR 1.5), arterial thromboembolism (OR 1.5), pulmonary disease (OR 1.4), and anemia (OR 1.4) all influence the risk of VTE in cancer patients.

Inherited or acquired hypercoagulable states are present in more than 20% of patients with VTE and occur at an even greater frequency in patients with idiopathic or recurrent VTE (see Table 16.1 ; see Chapter 14 ). Factor V Leiden is the most common inherited thrombophilic state, followed by the prothrombin gene G20210A mutation. Inherited deficiencies of endogenous anticoagulants such as antithrombin III, protein C, and protein S are more potent risk factors for VTE but much less common in the general population. Elevated levels of factors VIII, IX, or XI have also been associated with a modestly increased risk of VTE. Antiphospholipid syndrome (APLS) is an acquired form of thrombophilia that has been associated with an increased risk of initial and recurrent venous and arterial thromboembolism (see Chapters 14 and 20 ).

Hormonal therapies including combined estrogen-progestin oral contraceptives and estrogen replacement therapy are associated with a threefold to fourfold and twofold increased risk of VTE, respectively (see Chapter 31 ). The estrogen vaginal ring and transdermal estrogen, as well as depot medroxyprogesterone, also appear to be associated with increased risk. The low-dose progestin intrauterine device thus far has not been determined to be associated with increased risk.

Immobility is associated with a sixfold increased risk of VTE. Increased risk is also associated with infectious illnesses such as human immunodeficiency virus (HIV) and autoimmune disorders such as inflammatory bowel disease and systemic lupus erythematosus. Chronic hemolytic anemia such as sickle cell anemia and paroxysmal nocturnal hemoglobinuria are associated with an increased risk of VTE. Indwelling central venous catheters (CVCs), particularly common in critically ill patients, increase the propensity for venous thrombosis through a variety of mechanisms, including endothelial damage, blood flow impedance, and serving as a nidus for clot formation. Symptomatic CVC-associated DVT occurs in 2% to 6% of patients. The risk is even higher with peripherally inserted central catheters (PICCs), which are associated with thrombosis in 14% of critical care patients (see Chapter 30 ). Such catheters are associated with the majority of VTE in children (see Chapter 15 ). Obesity (defined as a body mass index [BMI] ≥ 30) is associated with an approximately twofold risk of VTE. Long-haul travel (>4 hours) is associated with a twofold to sixfold increased risk of VTE that amplifies with increasing duration of travel.

Venous Thromboembolism Prevention

Meta-analyses have demonstrated that pharmacologic VTE prophylaxis reduces the risk of symptomatic DVT, PE, and fatal PE by approximately 50% at the expense of a modest increase in major bleeding. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux have all been demonstrated to be effective in medically ill patients. Three times daily UFH may be associated with a greater risk of bleeding than is twice daily UFH. The direct oral anticoagulants (DOACs) such as apixaban, betrixaban, dabigatran, and rivaroxaban have demonstrated efficacy in VTE prevention in surgical and medically ill patients.

Large prospective multicenter surveys have demonstrated that VTE prophylaxis is underprescribed. Strategies that have been demonstrated to improve prescription of VTE prophylaxis and reduce VTE include computer alerts and mandatory clinical decision support smart order sets. However, prescription of VTE prophylaxis does not ensure its administration. Retrospective studies have demonstrated that 12% of prescribed doses of VTE prophylaxis are not administrated primarily due to refusal. In 5% of patients, 75% or more of prescribed doses of VTE prophylaxis are not administered. A retrospective study of general surgery and trauma patients found that omission of two or more doses of prophylaxis was associated with a significantly increased risk of VTE. Patient education and multifaceted unit-based initiatives to track performance have reduced missed doses of VTE prophylaxis. Availability of an oral agent for VTE prophylaxis has the potential to significantly reduce VTE prophylaxis nonadministration. Identification of the most effective strategy to increase VTE prophylaxis administration is an important patient safety priority.

It is important to note that VTE prophylaxis may not have a favorable risk:benefit ratio in all hospitalized patients. Several risk assessment tools have been developed for hospitalized medically ill and surgical patients. The Padua, Improve, and Caprini models have been validated in independent patient populations ( Table 16.2 to 16.4 ). However, a recent validation study found the discrimination characteristics of these risk stratification tools poor, so further investigation to identify the optimal VTE risk assessment tools for medical and surgical hospitalized patients is needed.

Pharmacologic VTE prophylaxis is associated with an increased risk of bleeding which may outweigh its benefits in some patients. The IMPROVE survey identified a number of variables associated with an increased risk of bleeding. The IMPROVE bleeding score was validated in a prospective enrolled independent patient population. For patients at increased risk for bleeding, intermittent pneumatic compression devices have been shown to reduce the risk of DVT. In contrast, graduated compression stockings (GCS) do not appear to reduce VTE but do increase the risk of skin complications. Because the risk of VTE associated with a hospital stay extends for weeks and the mean length of hospitalization is less than a week, determining which patients are likely to benefit from VTE prophylaxis after discharge is an important question that remains to be answered. In the future, validated VTE and bleeding risk assessment tools may help providers identify hospitalized patients who will benefit from VTE thromboprophylaxis during their inpatient stay and post discharge. Until then, providers are encouraged to assess the available risk assessment tools and incorporate these tools into their VTE prophylaxis ordersets (see Tables 16.2 to 16.4 ). ( Table 16.5 outlines available pharmacologic VTE prophylaxis options.)

Diagnosis

Recognizing the presence of VTE can be challenging because the signs and symptoms are neither sensitive nor specific for the diagnosis. Consequently, the most important step in diagnosis is maintaining adequate clinical suspicion. This goal is best achieved by careful attention to each patient's constellation of risk factors, symptoms, and signs. Although clinical assessment alone is inadequate to confirm the diagnosis of VTE, both clinical gestalt and clinical prediction rules are useful in establishing the pretest probability of disease in outpatients. Clinical pretest probability models such as the Wells criteria and PE rule-out criteria serve as the foundation for diagnostic algorithms for DVT and PE ( Tables 16.6 to 16.9 ).

Although most DVT begin in the calf, the presenting symptoms and signs are often not noted until more proximal veins are involved. The initial clinical manifestations of DVT may include warmth, erythema, swelling, and pain or tenderness and may be acute, progressive, or resolve spontaneously. Cellulitis, trauma, Baker cyst, or musculoskeletal pain can all cause signs and symptoms similar to those of acute DVT. However, it is important to note that the majority of DVT are asymptomatic.

Most patients with acute PE present with at least one of the following: dyspnea, pleuritic chest pain, tachypnea, or tachycardia. Other findings may include a loud pulmonic component of the second heart sound, fever, crackles, pleural rub, and/or wheezing. PE must always be considered in cases of unexplained dyspnea, syncope, or sudden hypotension. Symptoms and signs of PE are nonspecific and can be frequently seen in patients with other cardiopulmonary diseases, including pneumonia, chronic obstructive lung disease exacerbation, pneumothorax, myocardial infarction, heart failure, pericarditis, musculoskeletal pain or trauma, pleuritis, malignancy, and, occasionally, intraabdominal processes such as acute cholecystitis and nephrolithiasis.

Clinical pretest probability models are useful for assessing a patient's risk for VTE and determining the appropriate course for further evaluation. The most widely studied and validated models are the Wells score (see Tables 16.6 and 16.7 ) and the Geneva rule (see Table 16.8 ). The major distinction between these two preclinical probability models is that the Geneva rule consists of completely objective criteria, whereas the Wells score incorporates clinical judgment as to whether PE is the most likely etiology of the patient's symptoms. When these models were compared head to head, there were no major differences in diagnostic accuracy or negative predictive value for the exclusion of VTE. All scoring systems performed well in combination with d -dimer measurements to identify a low-risk population that did not require radiologic testing to exclude VTE. The Pulmonary Embolism Rule-out Criteria (PERC) is a clinical decision support tool developed by Kline and coworkers to identify outpatients presenting with chest pain who are thought to be at low risk for PE in whom further diagnostic testing can be avoided (see Table 16.9 ). A recent meta-analysis of 12 studies encompassing more than 14,000 patients confirmed the accuracy of the PERC. Consequently, the PERC has been included in the American College of Physician's Practice Guideline on the diagnosis of PE.

Quantitative plasma measurements of d -dimer (a fragment of cross-linked fibrin) have been extensively studied in patients with acute DVT and PE. Although multiple inexpensive d -dimer tests are available, rapid quantitative enzyme-linked immunosorbent assays (ELISAs) are preferred due to their high sensitivity. In conjunction with pretest probability models, sensitive ELISA d -dimer tests measurements have been demonstrated to safely exclude the presence of DVT and PE in outpatients judged to be at low risk for VTE. Unfortunately, d -dimer levels are elevated in a large number of common clinical conditions (including cancer, inflammation, infection, pregnancy, and recent surgery), which makes the test less useful in unselected and hospitalized patients. In these cases, objective radiologic testing is necessary to confirm/exclude the diagnosis. Because d -dimer levels increase with age, age-specific d -dimer cutoffs have been proposed to increase the utility of d -dimer testing in older adults. This approach has been noted in a meta-analysis by Schouten et al. to lead to increased specificity in individuals older than 50 years while maintaining excellent sensitivity.

Venous ultrasonography is the preferred noninvasive test for the diagnosis of symptomatic proximal DVT, where it has a weighted sensitivity and specificity of 95% and 98%, respectively. Therefore, in most cases, treatment can be withheld on the basis of a negative venous ultrasound. However, if the clinical suspicion is high, additional imaging such computer tomography (CT) or magnetic resonance (MR) venography should be considered, particularly in anatomic locations such as the thorax or pelvis, where venous compression with the ultrasound probe is not possible or ultrasound visualization of vessels is blocked by anatomic structures. Other limitations of venous ultrasonography include insensitivity for asymptomatic DVT and calf vein DVT, dependence on operator skill, and difficulty distinguishing acute from chronic DVT in symptomatic patients. CT and MR venography are being increasingly used to diagnose DVT. CT venography is particularly useful for identifying clots in pelvic, thoracic, and intraabdominal veins that are not accessible with compression ultrasound techniques. In addition, CT can be used to diagnose DVT and PE in a single study. MR venography also shares these advantages and can differentiate between acute and chronic disease yet does not expose patients to ionizing radiation. However, MR is expensive, time-consuming, nonportable, and restricted in patients with metallic devices or claustrophobia.

Contrast-enhanced chest computer tomography angiography (CTA) is the imaging procedure of choice for PE because it has the capacity to reveal emboli in the main, lobar, segmental, and subsegmental pulmonary arteries, as well other diseases of the thorax that can mimic PE. In patients with an intermediate or high probability of PE, an abnormal CTA has a positive predictive value of 92% and 96%, respectively. In patients with a low clinical likelihood of PE, normal findings on CTA have a 96% negative predictive value supporting the use of multidetector CTA as stand-alone imaging for suspected PE in the majority of patients. This modality can be used in combination with d -dimer to screen low to intermediate risk patients, with excellent negative predictive value. Unfortunately, 5% to 8% of CT angiograms are technically inadequate due to motion artifact or inappropriate contrast timing. In such an instance, additional diagnostic procedures should be performed, particularly in the context of a high clinical probability. When compared head to head with ventilation/perfusion (V/Q) scans, CTA was shown to identify more patients with PE, although the clinical significance of these additional PE has been questioned. CTA also has the advantage of rapid performance. Disadvantages of CTA include the risk of adverse reactions to contrast (such as anaphylaxis or nephrotoxicity) and lack of portability.

Although chest CTA is a superior imaging test for PE, V/Q scans are still used in patients with severe contrast allergies or those at high risk for nephrotoxicity. V/Q scans are typically interpreted as being normal, low, intermediate, or high probability for PE. A normal scan essentially excludes the diagnosis of PE. In the PIOPED study, when the clinical suspicion of PE was high, PE was present in 96% of patients with high-probability lung scans. However, in patients with a high clinical pretest probability for PE, 66% of patients with intermediate-probability scans and 40% of patients with low-probability scans were subsequently diagnosed with PE by escalation to pulmonary angiography. This emphasizes that low- and intermediate-probability V̇/Q̇ scans are frequently nondiagnostic when there is a high clinical suspicion for PE. However, in the setting of a low clinical pretest probability for PE, a normal- or low-probability V̇/Q̇ scan correctly excluded PE in more than 95% of cases.

MR imaging has excellent sensitivity and specificity and may allow the simultaneous detection of DVT and PE. However, MR angiography and MR venography are technically difficult and led to inadequate results in 52% of patients in the PIOPED III study. This modality should therefore only be considered in centers that routinely perform this study in patients with contraindications to standard testing.

Pulmonary artery angiography is a sensitive and specific test for confirming or excluding acute PE and remains the “gold standard” diagnostic technique. In 1111 cases from the PIOPED study, 3% of studies were nondiagnostic and 1% were incomplete, usually due to a complication. Major morbidity and mortality rates were 1% and 0.5%, respectively. Serious complications include respiratory failure (0.4%), renal failure (0.3%), and hemorrhage requiring blood transfusion. Pulmonary angiography is generally reserved for patients in whom less invasive testing has been nondiagnostic. To avoid the potential complications associated with angiography, lower extremity duplex ultrasound is often performed in lieu of angiography in the diagnosis of patients with suspected but unconfirmed PE as a positive study for DVT is a strong indication that a PE is also present and itself justifies anticoagulation therapy.

Cost-Effective Approach to Venous Thromboembolism Diagnosis

To minimize patient exposure to ionizing radiation and overall health care costs, contemporary VTE diagnosis integrates pretest probability models such as the Wells criteria and PERC, d -dimer testing, and imaging. In conjunction with d -dimer testing, the Wells criteria have been demonstrated to safely exclude VTE in outpatients with suspected thromboembolism. The PERC facilitate identification of low-risk patients in whom PE can be ruled out without imaging. A schematic depiction of the use of the Wells criteria and the Geneva score in conjunction with the PERC and d -dimer testing in the diagnosis of DVT and PE is displayed in Figs. 16.1 and 16.2 .