CHAPTER 74
Venous Thromboembolism
Evangelina Berrios-Colon, PharmD, MPH, BCPS, CACP • Rebecca Arcebido, PharmD, BCACP
Venous thromboembolic disease encompasses two closely linked conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT and PE are significant causes of morbidity and mortality in the United States and in other Western countries. Although the precise incidence in the general population is unknown, because 50% of patients having clinically silent disease, it is estimated that venous thromboembolism (VTE) affects 350,000 to 600,000 people in the United States each year with as many as 100,000 deaths per year (Lavorini et al., 2013). The estimated annual direct medical costs of managing the disease are well above $1 billion and growing. In September 2008, the Surgeon General put out a call to action to prevent DVT and PE and described these conditions as serious public health problems.
Although 75% to 80% of hospitalized patients with PE have image-demonstrated DVT, up to 50% of patients with PE have no DVT found by ultrasonography or contrast venography studies (van Langevelde et al., 2013). However, the actual figures are likely to be substantially higher, as silent PE can develop in up to 40% to 50% of patients with DVT. With the approval of several novel oral anticoagulants by the U.S. Food and Drug Administration (FDA), the treatment and prevention of VTE has evolved tremendously and patient-specific factors must be taken into consideration when choosing therapy.
ANATOMY, PHYSIOLOGY, AND PATHOLOGY
Anatomy and Physiology
The venous system of the lower extremities can be divided into the superficial and deep vein groups. The superficial venous system includes the greater and lesser saphenous veins and their tributaries. Perforating veins connect the deep and superficial venous systems. The deep veins found in the calf flow into the popliteal vein, which continues into the femoral vein. The femoral vein connects to the iliac venous system and then into the inferior vena cava. The inferior vena cava flows into the right atrium. From the right ventricle the pulmonary artery takes the blood flow into the lungs. Blood supply to the lungs is provided by the pulmonary circulation and by the systemic circulation via the bronchial arteries.
Clinical Pearls
The superficial femoral vein is part of the deep venous system.
The venous flow in the lower extremities is directed from he superficial to the deep veins. Bicuspid valves in the veins of the lower extremity direct the flow centrally. The flow from the periphery into the right side of the heart is aided by the contraction of the skeletal muscles, compressing the veins in the extremities. The greater veins are helped by the egative intrathoracic pressure generated during inspiration.
The normal pulmonary arterial tree consists of large elastic arteries, smaller muscular pulmonary arteries, arterioles, and capillaries. The elastic capacity of the pulmonary irculation allows accommodation of increases in blood flow without increasing pulmonary artery pressures (normal range 25/10 mmHg). However, if a significant obstruction of the pulmonary vascular bed occurs (generally >30%), an abrupt increase in the pulmonary artery pressure results; his may be poorly tolerated by the right ventricle, leading to pulmonary hypertension or acute decompensation Belohlávek, Dytrych, & Linhart, 2013).
Pathology
DEEP VEIN THROMBOSIS
More than 90% of clinically significant PEs originate from thrombosis of veins in the lower extremities. Thrombi can orm in the calf veins, popliteal vein, and more proximal veins of the iliofemoral venous system. In the late 19th century, a German pathologist, Rudolf Virchow, defined the pathophysiological factors promoting the formation of a hrombus: venous stasis, abnormalities of the vessel wall, and hypercoagulability. Risk factors for VTE are based on hese conditions, known today as Virchow’s triad.
DVT usually develops in proximity to the venous valves. Initially a “white thrombus” is formed by platelet aggregaion, followed by a “red thrombus” with fibrin deposition. The thrombus propagates by continued fibrin and platelet aggregation. Consequently, it either resolves within hours to days by the fibrinolytic system or undergoes organization with re-endothelization. If there is re-endothelization, the venous lumen narrows and distal venous valves become incompetent because of increased intraluminal pressure. Venous flow is directed into the superficial venous system during leg muscle contraction, leading to edema and impaired viability of subcutaneous tissues, and in the most severe cases venous stasis ulcers are formed. This phenomenon is known as the post-thrombotic syndrome (PTS).
Within 7 to 10 days, the actions of fibrinolysis or organization reach a stable state. Thus, the embolic risk is highest within the first few days of thrombus formation (Kearon et al., 2012).
PULMONARY EMBOLISM
If the whole thrombus or any portion of it dislodges before it organizes, it may be transported in the venous system to the right side of the heart and into the pulmonary circulation. The acute obstruction of pulmonary vessels by an embolus leads to hemodynamic and respiratory consequences. The most important hemodynamic complication is the acute increase in pulmonary vascular resistance, which in extreme cases can lead to acute right-sided heart failure and death. In addition to mechanical obstruction, vasoconstriction occurs as a result of the release of vasoactive amines (serotonin, thromboxane A2) and the stimulation of baroreceptors in the pulmonary artery wall.
A major respiratory consequence of PE is increased alveolar dead space due to obstruction of blood flow leading to segments of lung with high ventilation relative to perfusion. Both increased dead space and intrapulmonary or intracardiac right-to-left shunting of blood lead to hypoxemia. Tachypnea is caused by the stimulation of juxtacapillary irritant receptors. Release of serotonin may also cause bronchoconstriction, accounting for the wheezing sometimes detected in patients with PE.
Over several hours, atelectasis may develop as a result of loss of surfactant distal to the occlusion. Development of pulmonary infarction is uncommon because of the dual blood supply of the lungs. Infarction occurs in <10% of cases, usually only if concomitant heart or lung disease is present (e.g., left ventricular failure, mitral stenosis, chronic obstructive lung disease).
After the acute phase, most emboli undergo resolution by fibrinolysis. Some thrombi fail to resolve, presumably as a result of defects in the intrinsic fibrinolytic system or because they were very well organized before embolization (Belohlávek et al., 2013).
EPIDEMIOLOGY
VTE is relatively rare in the general population in the absence of predisposing conditions. It is perhaps the result of converging combinations of inherited and acquired thrombotic risk factors that cause an increased risk for VTE, including:
Age greater than 40 years
Prior history of VTE
Major surgery, especially orthopedic surgery of the lower extremities
Bed rest in excess of 5 days
Malignancy
Fracture of the pelvis, hip, or long bones
Paralytic stroke
Estrogen treatment, such as high-dose oral contraceptives
Pregnancy
Hypercoagulable states (lupus anticoagulant, protein C deficiency, protein S deficiency, antithrombin III deficiency, factor V Leiden, and prothrombin gene 20210A mutations)
Obesity
Congestive heart failure
Inflammatory bowel disease
Smoking
Myocardial infarction (Goldhaber, 2010)
There are some data to suggest that the incidence of VTE is higher in African Americans than Caucasians. Asian-Pacific Islanders and Hispanics have a 2.5- to 4-fold lower risk of VTE. The relatively low incidence of VTE in Asians and Hispanics has not been explained, but may relate to a lower prevalence of genetic factors predisposing to VTE. For example, the prevalence of factor V Leiden in Asian populations is 0.5% compared with 5% in Caucasian populations (Bounameaux & Rosendaal, 2011).
HISTORY AND PHYSICAL EXAMINATION
In the patient with suspected DVT or PE, the history should focus on potential patient risk factors, including:
Prior history of thromboembolic disease
Recent immobilization or long-distance travel
Estrogen use
Family history of thromboembolic disease or hypercoagulable states
Recent trauma or surgery
Although a thrombus can form in any part of the venous circulation, the majority begins in the lower extremities. Once formed, a venous thrombus may remain asymptomatic, spontaneously lyse, obstruct the venous circulation, propagate into more proximal veins, embolize, or act in any combination of these ways (Witt, 2011). Many patients with VTE may never even develop symptoms from the acute event. The symptoms of DVT or PE are nonspecific and objective tests are required to confirm or exclude the diagnosis.
Patients with DVT frequently complain of calf pain. DVT is suggested by unilateral leg swelling, warmth, or erythema. There may be tenderness or increased tissue turgor along the course of the involved vein. The patient may experience increased resistance or pain during dorsiflexion of the foot (known as a positive Homans’s sign). PTS, a long-term complication of DVT caused by damage to the venous valves, also produces similar symptoms, including chronic lower-extremity swelling, pain, tenderness, skin discoloration, and ulceration.
DIAGNOSTIC CRITERIA
Estimating the patient’s pretest probability for VTE is the first step in selecting a diagnostic pathway. Pretest probability initiates and guides the entire diagnostic testing process. Pretest probability arises from the history, the physical examination, and the clinician’s training and judgment. To objectively calculate a patient’s probability of VTE, several validated scoring tools have been developed. The Wells score is the most robust scoring system for categorizing the pretest probability for both PE and DVT. It divides probability into categories of high risk, moderate risk, and low risk to assist in guiding therapy (Table 74.1A, B).
Wells Criteria for Predicting Deep Vein Thrombosis |
FACTOR | POINTS |
Paralysis, paresis, or recent orthopedic casting of lower extremity | +1 |
Immobilization (≥3 days) within previous 4 weeks | +1 |
Localized tenderness in deep vein system | +1 |
Swelling of entire leg | +1 |
Calf swelling 3 cm greater than other leg (measured 10 cm below the tibial tuberosity) | +1 |
Pitting edema greater in the symptomatic leg | +1 |
Collateral nonvaricose superficial veins | +1 |
Malignancy (receiving treatment, treated in the past 6 months or palliative) | +1 |
Alternative diagnosis more likely than DVT (Baker’s cyst, cellulitis, muscle damage, superficial venous thrombosis, post-phlebitis syndrome, inguinal lymphadenopathy, external venous compression) | -2 |
PROBABILITY | SCORE |
High risk | >3 |
Moderate risk | 1–2 |
Low risk | 0 |
DVT, deep vein thrombosis.
Source: Adapted from Wells et al. (1997).
DIAGNOSTIC STUDIES
The D-dimer assay is a blood test frequently used in the diagnostic evaluation of patients suspected to have VTE. It is based on the principle that clots contain fibrin, which the body degrades naturally, spilling the D-dimer protein into the blood. Measurement of plasma levels of D-dimer has been used as a complementary test with IPG or ultrasound. If the level of D-dimer is below a certain cutoff point (usually 500 mg/L) and an imaging study is negative, the negative predictive value of the combination is 98.5% (Wells & Anderson, 2013). Its sensitivity for the diagnosis of VTE ranges between 83% to 96.8%, with specificity ranging between 45.1% and 68%. This precludes the use of the assay as a screening tool for patients with suspected PE, but it may be useful for patients with inconclusive nuclear scans. Patients with VTE may also have elevated erythrocyte sedimentation rate and white blood cell count.
