Etiology and Pathogenesis

A thrombus—that is, a blood clot—is the material that travels to the pulmonary circulation in pulmonary thromboembolic disease. Other material also can travel via the vasculature to the pulmonary arteries, including tumor cells or fragments, fat, amniotic fluid, and a variety of foreign materials that can be introduced into the circulation. This text does not consider these other (much less common) types of embolism, which usually have quite different clinical presentations than thromboemboli.

In the majority of cases, the lower extremities are the source of thrombi that embolize to the lungs. Although these thrombi frequently originate in the veins of the calf, propagation of the clots to the veins of the thigh is necessary to produce sufficiently large thromboemboli that can obstruct major portions of the pulmonary vascular bed and become important clinically. Rarely do pulmonary emboli originate in the arms, pelvis, or right-sided chambers of the heart; combined, these sources probably account for less than 10% of all pulmonary emboli. However, not all thrombi resulting in embolic disease are clinically apparent. In fact, only about 50% of patients with pulmonary emboli have previous clinical evidence of venous thrombosis in the lower extremities or elsewhere.

Three factors are commonly cited as potential contributors to the genesis of venous thrombosis: (1) alteration in the mechanism of blood coagulation (i.e., hypercoagulability), (2) damage to the vessel wall endothelium, and (3) stasis or stagnation of blood flow. In practice, many specific risk factors for thromboemboli have been identified, including immobilization (e.g., bed rest, prolonged sitting during travel, immobilization of an extremity after fracture), the postoperative state, congestive heart failure, obesity, underlying carcinoma, pregnancy and the postpartum state, use of oral contraceptives, and chronic deep venous insufficiency. Patients at particularly high risk are those who had trauma or surgery related to the pelvis or lower extremities, especially hip fracture or hip or knee replacement.

A number of genetic predispositions to hypercoagulability are recognized. They include deficiency or abnormal function of proteins with antithrombotic activity (e.g., antithrombin III, protein C, protein S) or the presence of abnormal variants of some of the clotting factors that are part of the coagulation cascade, especially factor V and prothrombin (factor II). The most commonly found genetic defect that causes hypercoagulability is called factor V Leiden. It is usually due to a single base pair substitution leading to replacement of an arginine residue by glutamine, causing the factor V protein to become resistant to the action of activated protein C. Individuals who are heterozygous for factor V Leiden have a threefold to fivefold increased risk for venous thrombosis. The much less common homozygous state confers a significantly higher risk. In the genetic variant of prothrombin often called the prothrombin gene mutation, there is also a single base pair deletion that appears to affect posttranslational mRNA processing, leading to increased plasma levels of prothrombin and predisposition to venous thrombosis.

Whereas deficiencies of the antithrombotic proteins (antithrombin III, protein C, and protein S) are rare, factor V Leiden may have a prevalence of up to 5%. The fact that it is found in some 20% of patients with a first episode of venous thromboembolism suggests it is an important risk factor. Both factor V Leiden and the prothrombin gene mutation are relatively common in the Caucasian population but rare among African Americans and Asians in the United States.

Pathology

Pathologic changes that result from occlusion of a pulmonary artery depend to a large extent on the location of the occlusion and the presence of other disorders that compromise O₂ supply to the pulmonary parenchyma. There are two major consequences of vascular occlusion in the lung parenchyma distal to the site of occlusion. First, if minimal or no other O₂ supply reaches the parenchyma, either from the airways or the bronchial arterial circulation, frank necrosis of lung tissue (pulmonary infarction) will result. According to one estimate, only 10% to 15% of all pulmonary emboli result in pulmonary infarction. It is sometimes said that compromise of two of the three O₂ sources to the lung (pulmonary artery, bronchial artery, and alveolar gas) is necessary before infarction results. Second, when parenchymal integrity is maintained and infarction does not result, hemorrhage and edema often occur in lung tissue supplied by the occluded pulmonary artery. The name congestive atelectasis has sometimes been applied to this process of parenchymal hemorrhage and edema without infarction.

With either pulmonary infarction or congestive atelectasis, the pathologic process generally extends to the visceral pleural surface, so corresponding radiographic changes often are pleura-based. In some cases, pleural effusion also may result. As part of the natural history of infarction, there is generally contraction of the infarcted parenchyma and eventual formation of a scar. With congestive atelectasis but no infarction, resolution of the process and resorption of the blood may leave few or no pathologic sequelae.

In many cases, neither of these pathologic changes occurs, and relatively little alteration of the distal lung parenchyma is found, presumably because of incomplete occlusion or sufficient nutrient O₂ from other sources. Frequently, the thrombus quickly fragments or undergoes a process of lysis, with smaller fragments moving progressively distally in the pulmonary arterial circulation. Whether this rapid process of clot dissolution occurs is important in determining the pathologic consequences of pulmonary embolism.

With clots that do not fragment or lyse, generally a slower process of organization in the vessel wall and eventual recanalization are seen. Webs may form within the arterial lumen and sometimes are detected on a pulmonary arteriogram or on postmortem examination as the only evidence for prior embolic disease.

Pathophysiology

When a thrombus migrates to and lodges within a pulmonary vessel, a variety of consequences ensue. They relate not only to mechanical obstruction of one or more vessels but also to the secondary effects of various mediators released from the thrombus and ischemic tissue. The effects of mechanical occlusion of the vessels are discussed first, followed by a consideration of how chemical mediators contribute to the clinical effects.

When a vessel is occluded by an embolus and forward blood flow through the vessel stops, perfusion of pulmonary capillaries normally supplied by that vessel ceases. If ventilation to the corresponding alveoli continues, it is wasted and the region of lung serves as dead space. As discussed in Chapter 1, assuming that minute ventilation remains constant, increasing the dead space automatically decreases alveolar ventilation and hence CO₂ excretion. However, despite the potential for CO₂ retention in pulmonary embolic disease, hypercapnia is an unusual consequence of pulmonary embolism, mainly because patients routinely increase their minute ventilation after an embolism occurs and more than compensate for the increase in dead space. In fact, the usual consequence of a pulmonary embolus is hyperventilation and hypocapnia, not hypercapnia. However, if minute ventilation is fixed (e.g., in an unconscious or anesthetized patient whose ventilation is controlled by a mechanical ventilator), a PCO₂ rise may result from the increase in dead space caused by a relatively large pulmonary embolus.

In addition to creating an area of dead space, another potential consequence of mechanical occlusion of one or more vessels is an increase in pulmonary vascular resistance. As discussed in Chapter 12, the pulmonary vascular bed is capable of recruitment and distention of vessels. Not surprisingly, experimental evidence indicates no increase in resistance or pressure in the pulmonary vasculature until approximately 50% to 70% of the vascular bed is occluded. The experimental model is somewhat different from the clinical setting, however, because release of chemical mediators may cause vasoconstriction and additional compromise of the pulmonary vasculature.

With further limitation of the vascular bed by the combination of mechanical occlusion and the effects of chemical mediators, the pulmonary vascular resistance and pulmonary artery pressure may rise so high that the right ventricle cannot cope with the acute increase in afterload. As a result, the forward output of the right ventricle may diminish, blood pressure may fall, and the individual may have a syncopal (fainting) episode or go into cardiogenic shock. In addition, “backward” failure of the right ventricle may occur, which manifests acutely with elevation of systemic venous pressure and appears on physical examination as distention of jugular veins.

The hemodynamic consequences of acute pulmonary embolism depend to a large extent on the presence of preexisting emboli and whether underlying pulmonary vascular disease or cardiac disease is present. When emboli have occurred previously, the right ventricular wall has already thickened (hypertrophied), and higher pressures can be generated and maintained. On the other hand, an additional embolus in an already compromised pulmonary vascular bed may act as “the straw that broke the camel’s back” and induce decompensation of the right ventricle.

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