Epidemiology

It is widely appreciated that the timely recognition of pediatric pulmonary thromboembolism (PTE) continues to lag despite recent strong efforts to broaden our understanding of thrombotic complications in children. Agreement on standardized treatment algorithms has been delayed by limited prospectively obtained clinical evidence, limited acceptance by some that the incidence is increasing and limited evidence for independent risk factors for PTE among hospitalized patients. These factors, combined with the presumably low incidence of PTE in children compared to adults and the lack of evidence that PTE are preventable, have slowed the development of guidelines on PTE diagnosis and prevention.

A related explanation may be that PTE has been rarely recognized as the primary explanation for death in pediatric patients. An old review of over 46,000 “routine” pediatric autopsies found “fatal” pulmonary emboli in 2.7%, and many of these cases dated from the preantibiotic era when deep and untreated infections were common, resulting in thrombophlebitis and septic emboli.

Occasionally, children dying from other fatal diseases are found to have clots in their lung tissue, but these are rarely assigned a primary role in the child’s demise. However, as more children survive with support from an indwelling central venous line (CVL), an understanding of the potential significance of multiple, though smaller, PTEs must be developed. The importance of fatal PTE is beginning to be recognized by forensic pathologists confronted with a child dying suddenly and unexpectedly. In addition, it is now accepted that previously, presumably, healthy children with unrecognized inherited thrombophilia, as well as children and adolescents with systemic lupus erythematosus (SLE) or malignancies are at small but unequivocal risk for PTE.

The age distribution of pediatric PTE shows bimodal peaks, in infancy and adolescence. The presence of a CVL is consistently recognized to play a critical role in PTE development, most commonly in the upper circulation (superior vena cava [SVC] and right atrium). Among both outpatients and in-patients, PTE is also often associated with clotting dysfunction defined as inherited thrombophilia; among inpatients, acquired and inherited thrombophilia contribute to venous thromboembolism (VTE) in general, especially among children with sepsis and myeloproliferative neoplasms.

In adults, the age-adjusted annual incidence of PTE is 10–20 per 10,000 ; in pediatrics, the annual incidence is estimated to be 0.14–0.49 per 10,000. Among sick newborns with CVL, the prevalence of deep vein thrombosis may be 80% or higher, but the incidence of clinically significant PTE is unknown. The overall incidence cited for PTE among hospitalized pediatric patients is 0.86–5.7 per 10,000 patient years. It should be emphasized that these incidence rate estimates are from retrospective reviews of data collected from many centers with variable propensities to consider the diagnosis of PTE. Data on the incidence of PTE in prospective studies are scarce, even among high-risk populations.

Adults with chronic thromboembolic disease of the lungs are at risk for pulmonary hypertension from nonlethal emboli showering the pulmonary arterial circulation. Pulmonary hypertension as a manifestation of chronic PTE is not often recognized in pediatric patients, either in published reports or from our personal experience. Perhaps this is because chronic PTE are rare, or, more likely, because more attention is paid to the higher pulmonary vascular resistance that occurs in the context of congenital cardiovascular malformations causing pulmonary overperfusion or to the effects of alveolar hypoxia in children with advanced lung disease who are often also supported with a CVL.

Etiology

One of the dicta regarding PTE in pediatric patients is that there is nearly always an explanation in up to 90% of cases, in contrast with adults where up to 30% of PTE are labeled idiopathic. In children, immobility leading to peripheral DVT is less often invoked than in adults, perhaps because they are less often immobile. After serious trauma involving the spine or lower extremities, and after orthopedic surgery, pediatric patients, particularly adolescents, develop PTE, and advice regarding routine care for these patients often includes, for example, pressure dressings for at-risk lower extremities.

As in adults, DVT and PTE have been linked to estrogen and progesterone use in patients 18 and younger. Injectable medroxyprogesterone and contraceptive patches are associated with an increased risk for eventual DVT.

Adults who are obese (body mass index [BMI] > 30 kg/m ² ) have a twofold increased risk for having PTE. Since 17% of children in the United States have a BMI greater than 95%, one would expect increased occurrence of PTE in these patients, but limited data exist, linking the obesity epidemic to more PTE in patients less than 18 years old, and the strength of the expected association is not yet clear. Prospective studies are needed in obese pediatric patients evaluating additional antecedent risk factors, such as established deep vein thrombosis or inherited thrombophilia, and these studies would serve to clarify an appropriate index of suspicion, particularly in obese adolescents.

Pathology/Pathogenesis

When death is attributed to PTE, the gross pathology is that of a clot, often twisted and branched, which occludes a large pulmonary artery. Very large clots can cause acute right heart failure. In adults, however, fatal PTE are macroscopic, yet not necessarily critically occlusive, and are believed to cause circulatory collapse, most likely because they elicit release of thromboxane, serotonin, histamine, thrombin, and related vasoactive substances from the vascular endothelium.

Very large clots in the pulmonary arterial circulation appear to cause sudden death with inadequate time for lung infarction to develop. The contribution of smaller PTE to nonlethal pulmonary infarction is likely but can only be speculated upon. In children, because deaths are rarely attributed to PTE as a primary cause, it is likely that understanding of the gross “pathology” of PTE in children will depend on imaging studies.

The microscopic picture of a PTE is that of a true thrombus arising in veins elsewhere. The clots are longer and more castlike than the typical arterial thrombus. Thrombi lodging in the pulmonary circulation are composed of platelets in various stages of senescence, red blood cells and white blood cells, in irregular shapes within a fibrin sheath.

In adults, PTE have arisen, most commonly, from thrombi in the venous circulation of the legs and from the pelvic veins during and after pregnancy. In children, trauma and surgery can also give rise to venous thrombi in the lower extremities. More commonly, however, the “upper” circulation is the site of thrombus origin as a complication of a CVL.

Imaging with computed tomography (CT) angiography suggests that segmental pulmonary arteries are the most common final site of PTE in children. In one report, over a third of images diagnostic for a PTE showed it in segmental arteries, followed by lobar and subsegmental arteries. Main pulmonary arteries, the most frequent site of fatal PTE, were the site for nonfatal PTE in only 9% of images.

The classic paradigm for the pathogenesis of thrombosis was suggested by Virchow in the 1840s. The causation of thrombi involves (1) Slowing of blood flow, (2) Changes in the vessel wall, and (3) “Susceptibilities” arising from the blood itself. Virchow’s triad still seems to be useful, and the venous circulation is a low-velocity system whose blood velocity is very sensitive to diminished cardiac output and the depth of breathing. Veins are relatively easily compressed during times of muscular inactivity. Unlike arterial atheromas, venous thrombi are often associated with demonstrable injury to the vascular intima. Changes in the venous wall can be induced, of course, by in-dwelling CVL, accidental or surgical trauma, and, primarily in the preantibiotic era, deep soft tissue or bone infections leading to septic thromboemboli. In children, developmental changes in the propagation of thrombi and inherited or acquired thrombophilias, described above and discovered over the last 30 years, would seem to qualify as “susceptibilities” in the blood itself predicted by Virchow over 150 years ago.

Clinical Features

It is likely that PTE is much more common than currently recognized. In our experience, PTE is rarely considered in pediatrics unless an at-risk patient has a sudden and severe worsening of his/her respiratory status, for example, a patient with lupus erythematosus. Clinicians rarely consider PTE as an explanation for gradual clinical decline. In an era when most patients with severe diseases are surviving, autopsies are less common than in times past. Except in those fatal instances of large, central clots, the absence of standard interpretive criteria undermines our ability to define whether smaller PTE seen at postmortem is incidental or instrumental in contributing to the child’s death.

Among adults and older pediatric patients able to articulate their symptoms, clinicians often recognize PTE symptoms retrospectively after diagnostic CT imaging. The symptoms are nonspecific, a “sense of unease,” and dyspnea. Pain is relatively late and occurs when the PTE causes significant ischemia or infarction to lung tissue close to the pleura. Though the pain is most often pleuritic, in adults, it is frequently first attributed to myocardial ischemia. In one series incorporating CT pulmonary angiography for patients aged 4 months to 18 years suspected of having a PTE, 52% described pleuritic pain, but pleuritic pain was equally common among patients suspected of having a PTE but with nondiagnostic CT angiography.

Symptoms eventually linked to PTE in infants and young children are nonspecific, e.g., irritability, poor feeding, and inactivity, and recognized in retrospect in patients with long-standing CVL or solid tumors of the mediastinum.

At all ages, shock, cyanosis, with low SpO ₂ %, and cardiovascular collapse are physical findings consistent with a very large PTE. Other common though nonspecific signs include tachypnea, rapid shallow breathing, and, in small children, chest wall retractions. When pleuritic pain can be described in older patients, physical signs arising from the PTE might include dullness to chest percussion, diminished breath sounds by auscultation, and a pleural friction rub. When diagnosing PTE, two considerations that are of paramount importance in patients of all ages are awareness of the underlying diagnosis and inspection of the patient’s extremities for a source of PTE. Finally, although PTE, in general, is rare in children, the prevalence may be as high as 15% among pediatric patients at high risk (see Table 60.1 ) who also have dyspnea, pleuritic pain, and the other findings of PTE.