Pathogenesis

Pulmonary emboli arise from detached portions of venous thrombi that form, in most cases, in deep veins of the lower extremities or pelvis (86%); the point of origin of pulmonary emboli is actually found in only one-half of patients.⁹ A small percentage of pulmonary emboli arise from the right-sided heart chambers (3.15%) or the superior vena cava (3%).⁹

Conditions that favor thrombus formation include blood stasis, the presence of hypercoagulable states, and vessel wall abnormalities (factors known as Virchow’s triad). Causes of blood stasis include local pressure, venous obstruction, and immobilization. Other causes of stasis include congestive heart failure, shock and dehydration, varicose veins, and enlargement of the right heart chambers. Several conditions enhance the intravascular coagulability of the blood and predispose to venous thromboembolic disease (Box 26-1).¹⁴ The most frequent causes of an inherited hypercoagulable state are the factor V Leiden mutation and the prothrombin gene mutation, which together account for 50% to 60% of cases.¹⁵ The major acquired risk factors for venous thromboembolism include recent major surgery, trauma, immobilization, antiphospholipid antibody syndrome, malignancy, pregnancy, oral contraceptives, and myeloproliferative disorders.¹⁶ Vessel wall abnormalities are found most often in patients who have sustained trauma or have undergone major surgery.

Pathology

Stasis, an important factor for the formation of DVT, is rarely the only risk factor.¹⁷ Deposition of platelets and fibrin in the venous valve cups of the lower extremities occurs as a result of stasis. The combination of diminished blood flow and the presence of trauma and toxins can worsen endothelial damage and promote the release of mediators that encourage adhesion, aggregation, and degranulation of platelets. The result is activation of the coagulation cascade and production of thrombi and fibrin.

PE is a frequent complication of DVT, occurring in more than 50% of cases with DVT confirmed on phlebography.¹⁸ PE occurs when a fragment of the thrombus in the venous system travels to the pulmonary circulation. Pulmonary emboli occur more frequently in the lower lobes and are more often found in the right lung than in the left lung, a phenomenon probably related to the flow distribution that favors the right lung and the lower lobes.⁶ Embolism to the pulmonary circulation produces pulmonary hemorrhage in the ischemic or infarcted lung in less than 10% of cases of PE. Infarction, secondary to thromboembolism, is less common in the lung than in other tissues because the lung has two blood supplies: the pulmonary arterial circulation and the bronchial circulation. At a capillary level, extensive connections exist within the pulmonary and bronchial circulations that prevent serious damage to lung tissue deprived of its pulmonary artery supply.⁶ Patients with underlying cardiovascular disease may have impairment of the remaining bronchial circulation with resultant lung tissue necrosis when emboli occur.

Pulmonary infarction is associated with thromboembolic obstruction of a medium-sized pulmonary artery. Generally, infarcts occur at the lung bases, are pleural-based, and may be accompanied by pleural effusion. Microscopic examination of the lung in pulmonary infarction shows necrosis of alveolar walls, alveoli filled with red blood cells, and a mild inflammatory response in the periphery.⁶

Pathophysiology

The sudden obstruction of a pulmonary arterial branch causes a decrease in or total cessation of blood flow to the distal area of the lung that leads to respiratory and hemodynamic alterations.¹⁹ In the appropriate context, massive PE should be suspected anytime there is unexplained hypotension accompanied by an elevated central venous pressure (jugular vein distention).²⁰ It is a catastrophic entity that frequently results in acute right ventricular failure and death. Death from massive PE is the result of cardiovascular collapse rather than of respiratory failure.

Embolic obstruction of the pulmonary artery increases the alveolar dead space, causes bronchoconstriction, and decreases the production of alveolar surfactant. Wasted or dead space areas occur when areas of the lung parenchyma are ventilated but not perfused. The response is to increase total ventilation (). The increased contributes to the sensation of dyspnea that accompanies PE. Bronchoconstriction from diminished carbon dioxide concentration, regional hypoxia, and the production of serotonin and histamine cause further ventilation/perfusion () mismatching.²¹

Not all patients with PE have significant arterial hypoxemia, but the presence of a widened alveolar-arterial oxygen (O₂) tension gradient and reduced PaO₂ are common. Hypoxemia develops because of mismatch, intrapulmonary shunt, and cardiogenic shock. Shock is caused by obstruction of the pulmonary vasculature by massive emboli or by numerous small emboli in the presence of cardiopulmonary disease. Cardiac output decreases, and O₂ delivery declines. With the decrease in O₂ delivery, the peripheral tissues increase O₂ extraction causing venous O₂ desaturation. In patients with significantly increased right heart pressures, intracardiac right-to-left shunt may develop when blood flows through a patent foramen ovale.19,21 In addition, the depletion of surfactant material as a result of embolic occlusion can lead to atelectasis and intrapulmonary shunt, which can cause hypoxemia.¹⁹

The main hemodynamic consequence of PE is increased resistance to blood flow caused by obstruction of the pulmonary arterial bed. The hemodynamic consequences are determined by the extent of the cross-sectional area of the pulmonary circulation involved, the underlying cardiopulmonary reserve, and the neurohumoral response to the embolism. Pulmonary hypertension occurs when 50% of the pulmonary vascular bed has been occluded.19,21 To maintain the same flow at a higher pressure, the right ventricle must work harder. The result is an increase in right ventricular work that causes the right ventricle to become dilated and ischemic. The thin-walled right ventricle is not designed to work with acute heavy pressure loads. When the mean pulmonary artery pressure increases to greater than 40 mm Hg during an acute first PE, the right ventricle fails, and hemodynamic collapse and death occur.²² The exact role of vasoconstriction in the pathogenesis of pulmonary hypertension is uncertain, but vasoconstrictors such as serotonin and thromboxane A₂ may also play a role in the development of pulmonary hypertension after acute PE.

Although the usual course of PE is to resolve rapidly (because the body lyses the embolism with endogenous fibrinolytic agents), permanent residual emboli do occur.²³ Massive emboli are likely to resolve within weeks, particularly in young patients. Overall, less than 10% of patients have perfusion defects after 6 weeks. Vascular patency is restored when the unresolved emboli organize or form scars against the vessel wall.

Clinical Features

A high index of suspicion for venous thromboembolism is crucial to make the diagnosis for patients at risk. No specific signs or symptoms indicate the presence of venous thromboembolic disease, and a significant proportion of patients are asymptomatic (32%).2,24 The physical findings of DVT in the lower extremities include erythema and warm skin in one-third of patients and swelling and tenderness in three-fourths of patients. In patients who have swelling above and below the knee, fever, and a history of immobility and cancer, the likelihood of finding DVT on a venogram is only 42%.²⁵

The most frequent symptoms in patients with confirmed PE are dyspnea, followed by pleuritic chest pain and cough (Table 26-2).²⁶ The onset of dyspnea is usually rapid, within seconds (46%) or minutes (26%).²⁶ Hemoptysis occurs in 13% to 20% of patients. The combination of dyspnea of sudden onset, fainting, and acute chest pain should raise suspicion of PE. In one study, this combination of symptoms was present in 96% of patients with confirmed PE compared with 59% of patients in whom PE was suspected but not confirmed.²⁷ In some patients, dyspnea lasts only a few minutes, and this episode may be wrongly dismissed as being trivial.^19,27–29

There are no characteristic physical findings of PE. The most frequent physical findings include tachypnea, rales on chest examination, and tachycardia. Similar to dyspnea, these signs may be short-lived. Other common physical findings include an accentuated pulmonary component of the second heart sound (loud P₂) consistent with pulmonary hypertension. Fever may be present in 54% of patients.27–29 Similar to what occurs in the diagnosis of DVT, less than 35% of patients in whom PE is clinically suspected actually have it.²

Because the clinical features are not specific and because treatment is anticoagulation (which carries risk of bleeding over time), confirming or excluding the diagnosis with appropriate testing is necessary, rather than committing the patient to long-term anticoagulation on the basis of clinical suspicion alone. However, unless there is a contraindication to anticoagulating the patient (e.g., recent bleeding, head trauma), anticoagulation is often begun when the diagnosis of PE is first suspected and continued until it is ruled out by tests. The rationale for this approach is that the mortality rate associated with PE is high soon after its occurrence.

Diagnostic Modalities

The diagnosis of venous thromboembolic disease relies on the diagnosis of DVT or PE. The absence of one condition does not exclude the other.

Testing for Lower Extremity Deep Venous Thrombosis

To evaluate the clinical pretest probability of DVT, the Wells criteria are frequently used. These criteria include the following clinical parameters: presence of cancer, immobilization, localized tenderness, swelling, edema, previous DVT, collateral superficial veins, and absence of an alternative diagnosis.³⁴ In cases in which there is a moderate to high pretest probability, several modalities could be used for diagnosing DVT in the extremities, such as compression ultrasonography, impedance plethysmography, and venography. In patients with low pretest probability of DVT and a negative D-dimer, further testing may be unnecessary.^31,35–37

Venography

Venography involves the injection of contrast dye into a foot vein to allow venous visualization by x-rays. It is the standard for the diagnosis of DVT. However, many problems with the test may be encountered, including inability to cannulate the vein; adverse reaction to contrast material; and, in a small percentage of patients, formation of deep venous thrombi. When results of noninvasive studies are negative, venography is recommended for the evaluation of patients at high risk in whom iliac or pelvic vein thrombus is suspected.

Impedance Plethysmography

Impedance plethysmography is a noninvasive method and measures electrical impedance to blood flow, which changes with inflation and deflation of a lower extremity cuff. The quality of the test is operator-dependent and requires that the patient be supine and lay still for at least 2 minutes. The test has a sensitivity and specificity of 91% and 96% for symptomatic proximal venous thrombi. A lower sensitivity of 65% has been reported.38,39

Compression Ultrasonography

Compression ultrasonography has proved to be sensitive and specific for the diagnosis of symptomatic proximal DVT. This test is noninvasive, portable, and accurate and is the modality of choice for the diagnosis of DVT. Compression ultrasonography combines B-mode scanning with a tightly focused pulse Doppler beam directed at the vessels of interest. DVT is diagnosed with the findings of venous noncompressibility, an echogenic filling defect, absence of Doppler flow, free-floating thrombus in the vein, and venous distention.⁴⁰ The most reliable sign of DVT is lack of compressibility of the vein, although a free-floating thrombus has the highest embolic potential (Figure 26-1). The sensitivity and specificity of compression ultrasonography in symptomatic patients vary between 95% and 100% for the detection of a proximal lower extremity thrombus.^40,41 Areas not well visualized with compression ultrasonography include the iliac veins, the superficial femoral veins in the adductor canal, and the calf veins. However, the accuracy of compression ultrasonography, even with the addition of color Doppler ultrasonography, is moderate to low for the detection of DVT in patients at high risk who do not have symptoms.⁴² These results suggest that ultrasonography, although sensitive and specific for the diagnosis of DVT, is not a good screening test for patients at high risk who do not have symptoms.

The increased incidence of upper extremity DVT poses diagnostic problems. Ultrasonography still may be the initial diagnostic test of choice, although venography is more commonly used for detection of thrombi in hidden areas that cannot be assessed with ultrasonography and in the evaluation of patients without symptoms who have negative findings with noninvasive modalities but have a high risk of DVT.

Testing for Pulmonary Embolism

Noninvasive tests for the diagnosis of PE include scan and helical or spiral computed tomography (CT) angiography scan of the chest. Either of these tests, depending on the resources available, may be the initial diagnostic examination if the presence of acute PE is clinically suspected.⁴³ Echocardiography can suggest the diagnosis (right ventricular dilation, dysfunction, or thrombus) and provide prognostic information.⁴⁴ In certain cases when these noninvasive tests are nondiagnostic, pulmonary angiography may be needed to confirm or exclude the diagnosis of PE.

scanning involves the inhalation of a radiolabeled gas (usually xenon-133, xenon-127, krypton-181m, or technetium-99m) and the intravenous injection of macroaggregated albumin tagged with a gamma-emitting radioisotope. The distribution of lung ventilation () and lung perfusion () is studied, and areas of mismatch where is less than are sought. The presence of mismatches most often indicates embolic occlusion of the blood vessel, although other rare causes of mismatches exist, such as extrinsic compression of the vessel by a mass, intraluminal obstruction by angiosarcoma, or obliteration of a vessel by vasculitis. The addition of scan increases the specificity of scan.⁴⁵ Generally, with the presence of a parenchymal abnormality, the defect coincides with the defect, and matched abnormalities are found. Normal results of a scan exclude the presence of a clinically significant PE in the context of a low clinical probability of PE. In these cases, anticoagulant therapy can be safely withheld.⁴⁶ Abnormal scan results can be classified as high probability, intermediate (or indeterminate) probability, and low probability for PE, according to the size of the defect and the degree of mismatch between the scan and chest radiographic abnormalities.⁴⁵ Diagnostic accuracy is greatest when scan results are combined with clinical probability (Table 26-3).⁴⁷ The presence of concomitant cardiopulmonary disease (e.g., COPD), even if severe, does not diminish the diagnostic usefulness of scans in the diagnosis of acute PE.^48–50

TABLE 26-3

Revised PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) Ventilation/Perfusion Scan Interpretation Criteria

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High probability	Two or more large (>75% of a segment) segmental defects without corresponding or abnormalities on chest radiograph
	One large segment defect and two or more moderate (25%-75% of a segment) segmental defects without corresponding or abnormalities on chest radiograph
	Four or more moderate segmental defects without corresponding or abnormalities on chest radiograph
Intermediate probability	One moderate or up to two large segment defects without corresponding defect or abnormalities on chest radiograph
	Corresponding defects and parenchymal opacity in lower lung zone on chest radiograph
	Corresponding defects and small pleural effusion
	Single moderate matched defects with normal findings on chest radiograph
	Findings difficult to categorize as normal, low, or high probability
Low probability	Multiple matched defects, regardless of size, with normal findings on chest radiograph