A 54-Year-Old Woman With Shortness of Breath: Part 1

Discussion. Pulmonary embolism is the result of embolic fragments of thrombus finding their way into the right ventricle before being expelled into the pulmonary arteries until being impacted due to the arborization of the pulmonary vasculature. Thus, the core pathogenesis involves first abnormal thrombus formation somewhere in the body, which is most common in the veins of the lower extremities and then into the lungs, creating areas of ventilation-perfusion mismatch. This occurs when areas affected by such emboli are being ventilated but not perfused. The result is a nasty combination of tissue hypoxia due to this alteration of pulmonary physiology, strain to the right heart that must work against increased resistance from the impacted emboli, and varying degrees of peripheral hypoperfusion due to decreased venous return and delivery of blood to the left ventricle.

Most emboli have their origin in the lower extremity veins, a fact demonstrated more than 50 years ago by fibrinogen-labeled nuclear scan studies.^1,2 This is an important consideration because acute or subacute history of comorbid conditions are associated with venous stasis in the lower extremities. We look for surgeries associated with general anesthesia of more than 30 minutes, hip and long bone fracture of the lower extremities, neurologic disability such as stroke, and perhaps hospitalization for any cause lasting longer than 3 days or so. Still, many patients with PE give no such history or a more mundane probable causation, such as a very long automobile or airplane trip.

The cardiac symptom most often associated with PE is shortness of breath, which is one of the more common symptoms in medicine. There are red flag-associated findings, which make PE more likely, including pleuritic chest pain, hemoptysis, and (rarely) syncope, which suggests a large PE, indeed.

Absent will be tag along symptoms besides shortness of breath, suggesting other diagnoses such as pneumonia (fever or cough with purulent sputum) or congestive heart failure (background history of orthopnea or pedal edema). Additionally, cardiac ischemia usually manifests a different qualitative form of chest pain.

Examination findings are similarly nonspecific from a variety of other chest pathology and include sinus tachycardia, tachypnea, and arterial hypoxemia. Indeed, a patient presenting with acute or subacute shortness of breath is a candidate for PE, even more so if arriving with the comorbid risk factors described above. But the diagnosis must be separated from other common and serious causes, which gets us to the current strategies used to confirm or exclude PE.

Although PE is a serious diagnosis, with a 20% mortality rate within 90 days of diagnosis, the PE is not the definitive cause of death. Rather, the risk factors that set it up—major surgery, prolonged hospital stays for cancer, stroke, congestive heart failure—are generally the causes associated with mortality. The actual PE causation for mortality of undiagnosed PE has been found to be about 5%. And viewing the prism in the opposite direction, the final diagnosis of PE in patients who come through the ER/urgent care as “rule out PE” is only 5% of cases.²

How do we create some order to properly diagnose patients presenting with a somewhat non-specific set of findings so as not to miss a very dangerous, yet treatable, illness, which has a non-trivial mortality when missed without anticoagulating very large numbers of patients?

That question has been nicely addressed in the last decade by solid studies using quickly obtainable data, which essentially quantitate degrees of risk for the presence of PE. Based on good specificity and sensitivity statistics of probability, these datapoints either exclude PE or point to a definite radiologic study—usually a CT angiogram—which, if positive, confirms PE and provides data of risk stratification used in therapy decisions.

Why not just proceed to angiography in all those patients suspected of PE? The answer is that there are two risk factors associated with CT angiography. First, there is significant dye load and radiation exposure, especially in the breasts, and particularly in younger patients. And second, as good as we have become with the ever-improving anticoagulants, including novel oral anticoagulants, anticoagulation still carries risk, to which we would be exposing a large number to patients.

There are two main scoring systems used to quantitate risk for PE, which have been validated in strong studies now incorporated in specialty guidelines, namely the Wells Score and the Geneva Score. The Wells Score, which is commonly used in the United States,⁴ assigns points for a variety of findings associated with PE risk and symptomatology.¹ Specifically, “clinicians’ implicit sense” that PE is the most likely diagnosis = 3 points; presence of signs/symptoms of deep vein thrombosis (DVT) = 3 points; heart rate greater than 100/min = 1.5 points; in prior 4 weeks immobilization greater than 3 day or surgery = 1.5 points; previous PE or DVT = 1.5 points; hemoptysis = 1 point; and active cancer = 1 point. If a Wells Score is above 4, the clinician should proceed to imaging to confirm or exclude PE.^3,4

The second core study that greatly aids the diagnosis is the D-dimer assay. D-dimer is a piece of a blood clot, specifically crosslinked fibrin, that is a product of clot formation somewhere in the body that has been or is being lysed by the fibrinolytic system.⁴ The assumption is D-dimer presence in large amounts is being derived from lysed pulmonary and DVT. But D-dimer is not totally specific for this and occurs post-operatively and with COVID-19 infection.^4,5 This affects the specificity of the finding.

Still, several well-validated studies confirm that a normal D-dimer has sensitivity between 96% to 98%, such that negative D-dimer testing essentially rules out PE.³ In clinical practice, we generally combine these two maneuvers: calculating Wells (or Geneva) Scores and age-adjusted D-dimer testing to either exclude PE or proceed to imaging for definitive diagnosis. A final note on the imaging: as someone who participated in Dr Sol Sherry’s pulmonary embolism trials in the late 1960s and early 1970s, it is very interesting to see the reappearance of the ventilation-perfusion scan using modern-day Spect technology, which demonstrates the ventilation-perfusion mismatches described previously at a far lower radiation exposure.⁶

Differential diagnoses. Answer D is incorrect, since up to 80% of PE suspects in the ER setting will have that diagnosis excluded by Wells Score analysis and D-dimer testing and will not benefit from imaging studies.³ Our patient’s data compute to a Wells Score of 4.5, which was accompanied by a very high D-dimer. These scores do not exclude PE, making answer C incorrect. The current schema is to now proceed to imaging (answer A), which will help stratify risk and determine which therapeutics should be used. Regarding answer B, the WELLS score here of 4.5 is suggestive of PE but not adequate for definitive diagnosis and commitment to anticoagulation. The score above 4.0 is high enough for proceeding to the definitive study of CT angiography.

What’s the Take Home? Pulmonary embolism is a serious condition wherein embolic fragments, usually arising from DVT in the lower extremities, are shed into the venous system and right ventricle, then into the pulmonary vasculature where they become impacted and create ventilation-perfusion mismatching, right ventricular strain, and decreased left ventricle filling. Comorbid conditions predisposing to DVT, such as long bone/hip fracture, prolonged bed rest from other illness, surgery with general anesthesia, and very long automobile/airplane trips, are important underlying conditions and clues to the presence of PE. Typical findings are symptoms of unexplained shortness of breath, less often accompanied by pleuritic chest pain, hemoptysis, and in severe situations, syncope. Sinus tachycardia and arterial hypoxemia are usual associated findings. Well-validated clinical scoring systems, like the Wells Score, together with D-dimer testing help clinicians either exclude PE in most patients in the outpatient setting and/or select those who require imaging studies to confirm or exclude this important diagnosis.

Patient follow-up. A pulmonary CT angiogram study was performed and confirmed PE. Specifics of that study and therapy ramifications will be addressed in Part 2 of A 54-Year-Old Woman With Shortness Of Breath.