Anastasia Alenova; Will Carter; Thémis Halka; Jackie Man; Pia Skok; Ayoush Srivastava; Annie Szeto

What is a PE?

Thrombosis is a term for the formation of a blood clot in a vessel. This clot, called a thrombus, consists mainly of fibers of protein and red blood cells knotted together in tight, firm clumps. When a thrombus forms in a ‘deep vein’ – for example, in the calf – it is called deep vein thrombosis (DVT). DVT _­­­­­typically begins in the pocket behind the valves of a vein, growing as more red blood cells get stuck and debris accumulates.¹

Occasionally, a part of the DVT breaks off and enters the blood stream; this is called an embolus. An embolus can be especially dangerous, as it travels in the blood and eventually gets lodged in a smaller blood vessel. This results in an occlusion (a blockage) that impedes blood flow.

Pulmonary embolism (PE) describes the specific case in which an embolus occludes a vessel and impedes blood flow in the lungs. In this case, an embolus detaches from a DVT in one of the large veins flowing towards the heart. The embolus is whisked along with the blood flow in the vein, through the right side of the heart, and into the blood vessels (pulmonary arteries) of the lungs where it can acutely increase the pressure felt by the heart.²

PE severity classification:

The severity of acute PE is characterized according to its hemodynamic consequences, or how it impacts blood flow. The most important prognostic factor is blood pressure, as normotensive patients generally have good prognoses while patients presenting with hypotension often have grave prognoses.³ Accordingly, high-risk PE (also referred as massive PE) is the most severe form of acute PE. It is characterized by a systemic hypotension (i.e. a low systolic arterial pressure) or by the occurrence of shock,⁴ when tissues are depleted of nutrients and oxygen, possibly as a result of hypotension.⁵

One major consequence of PE is the rise of pulmonary pressure, due to the occlusion of the pulmonary artery. This impacts the heart, especially the right ventricle, which has to work harder to maintain blood flow despite the occlusion. This acute pulmonary hypertension can lead to right ventricular (RV) dysfunction, another measure of the severity of PE.⁶ Normotensive patients are separated into two categories, depending on evidence of RV dysfunction:³ intermediate-risk (also referred as submassive) in the presence of RV dysfunction, and low-risk (nonmassive) otherwise.³  Of the normotensive patients on presentation, between 27-56% present with RV dysfunction,⁶ which is associated with a two-fold increase in mortality in the three months after PE diagnosis.²

Mortality rates increase from low-risk PE (up to 1%) to intermediate-risk PE (5-25%). In high-risk PE, mortality reaches between 18-65%.⁷

Who is at risk?

PE is the third most common cause of cardiovascular death, after coronary artery disease and stroke, with an estimated incidence rate of 60 to 70 per 100,000 people.⁷ Some studies report an incidence rate of 0.27% per year for patients over 20 years of age.⁸ Actual figures may be higher due the fact that PE can lead to sudden death, before a diagnosis of PE can be made.^7,8 PE incidence rates are related to age and sex, with some sources also proposing ethnicity as a factor.⁹

Acute PE predominantly occurs in middle-aged and elderly people, with incidence increasing with age.⁹ The highest prevalence is between 60 and 70 years of age,⁷ though autopsy studies suggest the highest incidence of PE is among 70- to 80-year-olds.⁷ After 65 years of age, certain healthcare institutions note a sharp decline in incidence rates. This could be caused by alternative diagnoses masking PE symptoms in the elderly.^8-9

Epidemiological studies suggest that the incidence of PE may also be related to sex, with higher rates in men than women.^8,10-11 Certain studies claim that under 55 years old, the trend is reversed, with a higher incidence of PE in females.⁴ Outpatient data, however, tends to support similar prevalence amongst both sexes.^8,10-11 Discrepancies in the data could be attributed to the differing clinical presentation of PE in men and women.¹¹

African Americans tend to have a slightly higher incidence rate compared to White populations, at 0.26% versus 0.21% respectively, especially over the age of 65.^8,10 Asian or Pacific patients, on the other hand, have lower risks of thromboembolism.^8,10 Further investigation is needed to confirm these trends and elucidate their biological mechanism.

Triggers and risk factors:

Most commonly, the blood clot behind a PE originates in a deep vein such as that of a leg, arm, or the pelvis. In some cases, PE can also be caused by other substances – including small masses of infectious material, fat, air bubbles, tumors, or amniotic fluid – that get trapped in a pulmonary artery.¹²

Although anyone can develop a PE, there are certain factors that increase risk. These can be grouped into inherited or acquired risk factors. Inherited risk factors include factor V Leiden disorder, prothrombin gene mutation (factor II disorder), and deficiencies in coagulation inhibitors – all of which increase the likelihood of blood clot formation.¹³ Certain conditions such as cancer and COVID-19, which are grouped under acquired factors, also put people at increased risk of PE. Another major acquired risk factor is surgery. Blood clots are also much more frequent during periods of inactivity, such as bed rest, hospitalization and, to a lesser extent, long trips. In both cases, blood flow to the legs slows down, promoting clot formation. Other acquired risk factors include obesity, supplemental estrogen, pregnancy, and smoking.¹⁴

Treatment:

PE is treated by preventing clot growth and new clot formation; restoring pulmonary blood flow; and preventing future recurrences.¹⁵ Patients who are diagnosed with PE are typically categorized by severity (as described above), and this risk classification helps inform the course and urgency of their treatment.¹⁵

Nearly all patients undergo initial treatment with anticoagulation drugs, such as direct-acting oral anticoagulants (e.g. apixaban, rivaroxaban), low molecular weight heparin (LMWH), fondaparinux, and vitamin K antagonists like warfarin.¹⁵ These drugs prevent the growth of any existing clots, and the formation of new clots. Direct acting oral anticoagulants are now the most commonly used medications to treat PE. They are pills taken once or twice a day, do not require monitoring or drug levels, and have few interactions with foods or other drugs. LMWH is given as an injection below the skin once or twice a day. Vitamin K antagonists like warfarin block the production of certain clotting factors in the liver, and are given alongside LMWH drugs for at least the first five days until they reach a therapeutic level.¹⁵ LMWH may be given long-term if a patient is pregnant or has cancer.¹⁵ For a patient who had a PE but has reversible risk factors, clinicians recommend taking antagonists for at least three months.¹⁵ Patients without a reversible risk factor are usually treated for at least six months, and maybe indefinitely. By following the necessary courses of treatment for the required time, the risk of a future PE is dramatically reduced, protecting patients for the long-term.  

Patients who are categorised high-risk may be treated aggressively with either thrombolytic (clot-dissolving) drugs or embolectomy (removal of clot).¹⁵ Patients with low bleeding risk may be given systemic thrombolytic therapy, but this treatment can have severe side-effects like sudden and severe bleeding.¹⁵ Clots can also be dissolved by applying an infusion of the thrombolytic drug directly into the thrombus (catheter-directed thrombolysis), or removed via more invasive procedures like surgical or catheter embolectomy.¹⁵ Embolectomy procedures are generally reserved for life-threatening cases when thrombolytics are contraindicated. Pulmonary Embolism Response Teams (PERTs) are multidisciplinary groups of experts that can help determine which patients require advance therapy like thrombolysis or embolectomy.

Low-risk patients may be admitted to the hospital, but are increasingly discharged to receive outpatient treatment.¹⁵ Intermediate-risk patients are generally admitted into hospitals for anticoagulant (blood thinner) therapy, monitoring, and potentially thrombolytic treatment.

After discharge from the hospital or emergency department, all PE patients should receive regular visits to their doctor to manage their medications, prevent and treat any medical complications during recovery.

References:

1. Kesieme E, Kesieme C. Deep vein thrombosis: a clinical review. Journal of Blood Medicine. 2011 Apr; 59.
2. Tapson VF. Acute Pulmonary Embolism. New England Journal of Medicine. 2008 Mar 6; 358(10): 1037–52.
3. Sekhri V, Mehta N, Rawat N, Lehrman SG, Aronow WS. Management of massive and nonmassive pulmonary embolism. Arch Med Sci. 2012; 8(6): 957-969. doi: 5114/aoms.2012.32402
4. Torbicki A, van Beek EJR, Charbonnier B, et al. Guidelines on diagnosis and management of acute pulmonary embolism. Task Force on Pulmonary Embolism – European Society of Cardiology. Eur Heart J. 2000; 21: 1301–36.
5. Mayo Clinic. Shock:First aid. 2021. Available at:  https://www.mayoclinic.org/first-aid/first-aid-shock/basics/art-20056620 [Accessed 14^th Oct 2021]
6. Ruigrok D, Noordegraaf A. Pathophysiology of acute pulmonary embolism. ESC CardioMed. 2018: 2756-2758. Available from: https://oxfordmedicine.com/view/10.1093/med/9780198784906.001.0001/med-9780198784906-chapter-657 [Accessed 23th Nov 2021]
7. Bĕlohlávek J, Dytrych V, Linhart A. Pulmonary embolism, part I: Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. Experimental and clinical cardiology 2013;18(2):129-138.
8. Stein PD, Patel KC, Kalra NK, Petrina M, Savarapu P, Furlong JW, et al. Estimated Incidence of Acute Pulmonary Embolism in a Community/Teaching General Hospital. Chest 2002 Mar;121(3):802-805.
9. Stein PD, Huang H, Afzal A, Noor HA. Incidence of Acute pulmonary embolism in a general hospital: Relation to age, sex, and race. Chest 1999;116(4):909-913.
10. Ouellette Daniel R, Harrington Annie. Is pulmonary embolism (PE) more common in men or women? 2020; Accessed Oct 21, 2021.
11. Robert‐Ebadi H, Le Gal G, Carrier M, Couturaud F, Perrier A, Bounameaux H, et al. Differences in clinical presentation of pulmonary embolism in women and men. Journal of thrombosis and haemostasis 2010 Apr;8(4):693-698.
12. Stanford Healthcare. Pulmonary embolism causes. Available from: https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/pulmonary-embolism/causes.html [Accessed 10^th Oct 2021].
13. Tarbox, A. K. and Swaroop, M. Pulmonary embolism. International Journal of Critical Illness & Injury Science. 2013; 3 (1): 69-72. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665123/ [Accessed 10^th Oct 2021].
14. Mayo Clinic. Pulmonary embolism. Available from: https://www.mayoclinic.org/diseases-conditions/pulmonary-embolism/symptoms-causes/syc-20354647 [Accessed 10^th Oct 2021].
15. Lavorini F, Di Bello V, De Rimini ML, Lucignani G, Marconi L, Palareti G, et al. Diagnosis and treatment of pulmonary embolism: a multidisciplinary approach. Multidiscip Respir Med. 2013;8(1):75.