COVID-19-associated pulmonary embolism

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usman Ali Akbar, M.B.B.S.[2]

Synonyms and Keywords: 2019 novel coronavirus disease, COVID19, Wuhan virus, pulmonary embolism, venous thromboembolism

Overview

In May 2020, various autopsies studies revealed pulmonary embolism to be the common cause of death in COVID-19 infected patients. The patients studied were in their mid-70s and had preexisting medical conditions such as cardiac diseases, hypertension, diabetes, and obesity. These studies highlight the role of hypercoagulability as a main contributor of the fatality in these patients. To support his theory, various studies have described Virchow's triad to be the main component of the hypercoagulable state in these patients.

Screenshot.273.jpg

Historical Perspective

Classification

Acute Pulmonary Embolism

  • Pathologically an embolus is said to be acute when it is situated centrally within the vascular lumen, or in other cases, it causes an occlusion of the vessel. It can cause an immediate occurrence of symptoms.

Chronic Pulmonary Embolism

  • An embolus is said to be chronic if it is eccentric and lies within the vessel wall.
  • It occludes the lumen of the vessel wall by more than 50%.
  • There is also evidence of recanalization within the thrombus.
  • Chronic thromboembolism can cause pulmonary hypertension especially when there are >3 months of effective anticoagulation therapy and one of the following criteria:
    • Mean pulmonary arterial pressure greater than or equal to 25 mmHg.
    • Pulmonary arterial wedge pressure less than or equal to 15 mmHg.
    • Abnormal lung V/Q scan or imaging findings suggestive of a chronic pulmonary embolism on CTPA, CMR, CPA.

Pathophysiology

  • As data on COVID-19 has been incomplete and evolving, the pathogenesis of pulmonary embolism has not yet been completely understood. Various contributors to the pathogenesis of pulmonary embolism in these patients are listed in the table below:
Pathology Description of the underlying mechanism
Endothelial cells dysfunction[2]
  • It has been proposed that endothelial cells contribute towards the initiation and propagation of ARDS by changing the vascular barrier permeability, increasing the chance of procoagulative state that leads to endotheliitis and infiltration of inflammatory cells in the pulmonary vasculature.
  • It has been proposed that COVID-19 can directly affect endothelial cells leading to widespread endotheliitis. SARS-CoV-2 also binds to the ACE2 receptors which alter the activity of ACE2.
  • Reduced ACE2 activity leads to activation of the kallikrein-bradykinin pathway, which increases vascular permeability.
  • The activated neutrophils migrate towards the pulmonary endothelial cells and produce cytotoxic mediators including reactive oxygen species.
Stasis
Hypercoagulable state[3]
Cd-PE-pathogenesis-temp.jpg

Causes

  • Recently, SARS-CoV-2 has been associated with pulmonary embolism and other coagulopathic disorders. Other than SARS-CoV-2, pulmonary embolism can be caused by a number of different factors:
Etiologies of Pulmonary Embolism
Hereditary Causes Comorbidities Miscellaneous
Factor V Leiden Mutation Heart failure Surgery
Protein C & S deficiency Congenital heart disease Pregnancy
Antithrombin deficiency Antiphospholipid syndrome OCPs
Obesity Immobilization
Myeloproliferative Disorders Trauma
Paroxysmal nocturnal hemoglobinuria Malignancy

Differentiating Pulmonary Embolism from other Diseases

Epidemiology and demographics

  • Various case reports and case series report relatively high incidence of pulmonary embolism in ICU patients.
  • The incidence of thrombotic complications is reported to be 31% in one study. In this study pulmonary embolism was the most common thrombotic complication.[4]
  • According to another study, there was found to be an overall 24% cumulative incidence of pulmonary embolism in patients with COVID-19 pneumonia, 50% (30–70%) in ICU and 18% (12–27%) in other patients.[5]
  • In the non-ICU settings (in-patient), pulmonary embolism is reported to occur in 3% of patients in one study.[6]
Incidence/Prevalence of Pulmonary Embolism in COVID-19 Patients
Date of Publication Author Country/Setting Total Number of Patients Incidence/Prevalence Reported
04 May 2020 Julie Helms et. al[7] France (ICU) 150 Prevalence : 16.7%

Incidence : 25 %

27 May 2020 Artifoni, M.[8] France (Non-ICU) 71 Incidence : 10 %
6 June 2020 Edler, C.[9] Germany 76 21%
31 May 2020 Faggiano, P. [10] France 21 33 %
02 June 2020 Hékimian, G.[11] France 51 16 %

Age

The data regarding age predilection is currently insufficient and shows no significant age difference in the development of pulmonary embolism in COVID-19 patients.

Gender

There is no significant predilection for the development of pulmonary embolism in a specific gender who are COVID-19 positive. However, some studies do report increased risk in male patients. [12]

Race

There is no racial predilection for the development of pulmonary embolism in COVID-19 patients.

Risk Factors

  • Multivariate analysis showed the following risk factors that predispose a patient of COVID-19 to pulmonary embolism:[13]
Risk factors for COVID-19 associated pulmonary embolism

Natural History,Complications and Prognosis

Complications

Prognosis

  • COVID-19 patients presenting with pulmonary embolism have a poor prognosis.
  • It has been reported that despite adequate anticoagulation being advised to patients in ICU, there is still relatively high incidence of PE in these patients.
  • Few studies showed VTE to be the main cause of death in COVID-19 patients which suggests setting a lower threshold for diagnostic imaging for DVT or PE.

Diagnosis

Pe approach to diagnosis-wikidoc.jpg

History and Symptoms

  • COVID-19 patients are usually at high risk of hypercoagulability and as there is an increased incidence of pulmonary embolism in ICU patients, they mostly have overlapping symptoms with pneumonia, ARDS, and sometimes present only with fever progressing to pulmonary embolism and sudden cardiac arrest.
  • Pulmonary embolism has a range of symptoms presentations, a patient could present with no symptoms, in shock or even sudden cardiac arrest.
  • The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) trial observed the following most common symptoms:[14]
    • Dyspnea that is sudden in onset at rest or exertion (73%)
    • Pleuritic pain (44%)
    • Calf or thigh pain (44%)
    • Calf or thigh swelling (41%)
    • Cough (34%)

Physical Examination

  • On physical examination following signs can be demonstrated in COVID-19 patients.[14]
General
Cardiac examination
Lung examination
DVT signs
  • Calf or thigh
  • Calf and thigh
Laboratory findings
X-ray

Echocardiography or Ultrasound

  • To view the echocardiographic findings on COVID-19, click here.

CT scan

  • To view the CT scan findings on COVID-19, click here.

MRI

Other Imaging Findings

CTPA & Ventilation Perfusion Scan
Right-sided segmental and subsegmental pulmonary arterial filling defects (yellow arrows) in keeping with acute distal pulmonary emboli. Source: Dr. Gianluca Martinelli

Other Diagnostic Studies

  • To view other diagnostic studies for COVID-19, click here.

Treatment

Medical Therapy

  • Different treatment strategies for COVID-19 patients suffering from pulmonary embolism are given in the table below:
Different treatment options Details
Prophylaxis
  • All hospitalized patients with COVID 19 should get proper venous thromboembolism prophylaxis in the absence of any contraindication of anticoagulation. However, the data is still controversial regarding this strategy as stated by the American Society of Hematology (ASH) and the Global COVID-19 Thrombosis Collaborative Group, demonstrating improved outcomes are lacking and it may also increase the risk of bleeding.
  • Some centers suggest the following:[16]
    • In an ICU setting, empiric use of intermediate or therapeutic dose anticoagulation should be instituted.
    • In a non-ICU setting, all hospitalized patients should be treated with prophylactic low dose molecular weight heparin.
Acute Pulmonary embolism
Outpatient treatment[17]
  • Critically ill patients that have recovered from COVID-19 and had a documented VTE are usually given a minimum of 3 months of anticoagulation.
  • Patients not admitted to hospitals but at risk of VTE, such as prior VTE episode, recent surgery, prolonged immobilization are usually given a prophylactic dose of Rivaroxaban 10 mg daily for 31 days or 39 days.
Cd-anticoagulation.jpg

Primary Prevention

  • The best way to prevent being infected by COVID-19 is to avoid being exposed to this virus by adopting the following practices for infection control:
    • Often wash hands with soap and water for at least 20 seconds.
    • Use an alcohol-based hand sanitizer containing at least 60% alcohol in case soap and water are not available.
    • Avoid touching the eyes, nose, and mouth without washing hands.
    • Avoid being in close contact with people sick with COVID-19 infection.
    • Stay home while being symptomatic to prevent spread to others.
    • Cover mouth while coughing or sneezing with a tissue paper, and then throw the tissue in the trash.
    • Clean and disinfect the objects and surfaces which are touched frequently.
  • There is currently no vaccine available to prevent COVID-19.

Secondary Prevention

  • The secondary prevention measures of Coronavirus disease 2019 (COVID-19) constitute protective measures to make sure that an infected individual does not transfer the disease to others by maintaining self-isolation at home or designated quarantine facilities.
  • Patients not admitted to hospitals but at risk of VTE, such as prior VTE episode, recent surgery, prolonged immobilization are usually given a prophylactic dose of Rivaroxaban 10 mg daily for 31 days or 39 days.

References

  1. Wichmann, Dominic; Sperhake, Jan-Peter; Lütgehetmann, Marc; Steurer, Stefan; Edler, Carolin; Heinemann, Axel; Heinrich, Fabian; Mushumba, Herbert; Kniep, Inga; Schröder, Ann Sophie; Burdelski, Christoph; de Heer, Geraldine; Nierhaus, Axel; Frings, Daniel; Pfefferle, Susanne; Becker, Heinrich; Bredereke-Wiedling, Hanns; de Weerth, Andreas; Paschen, Hans-Richard; Sheikhzadeh-Eggers, Sara; Stang, Axel; Schmiedel, Stefan; Bokemeyer, Carsten; Addo, Marylyn M.; Aepfelbacher, Martin; Püschel, Klaus; Kluge, Stefan (2020-05-06). "Autopsy Findings and Venous Thromboembolism in Patients With COVID-19". Annals of Internal Medicine. American College of Physicians. doi:10.7326/m20-2003. ISSN 0003-4819.
  2. Teuwen, Laure-Anne; Geldhof, Vincent; Pasut, Alessandra; Carmeliet, Peter (2020-05-21). "COVID-19: the vasculature unleashed". Nature Reviews Immunology. Springer Science and Business Media LLC. doi:10.1038/s41577-020-0343-0. ISSN 1474-1733.
  3. Panigada, Mauro; Bottino, Nicola; Tagliabue, Paola; Grasselli, Giacomo; Novembrino, Cristina; Chantarangkul, Veena; Pesenti, Antonio; Peyvandi, Fora; Tripodi, Armando (2020-04-17). "Hypercoagulability of COVID‐19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis". Journal of Thrombosis and Haemostasis. Wiley. doi:10.1111/jth.14850. ISSN 1538-7933.
  4. Klok, F.A.; Kruip, M.J.H.A.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.A.M.P.J.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.A.M.; Huisman, M.V.; Endeman, H. (2020). "Incidence of thrombotic complications in critically ill ICU patients with COVID-19". Thrombosis Research. Elsevier BV. 191: 145–147. doi:10.1016/j.thromres.2020.04.013. ISSN 0049-3848.
  5. Bompard, Florian; Monnier, Hippolyte; Saab, Ines; Tordjman, Mickael; Abdoul, Hendy; Fournier, Laure; Sanchez, Olivier; Lorut, Christine; Chassagnon, Guillaume; Revel, Marie-pierre (2020-05-12). "Pulmonary embolism in patients with Covid-19 pneumonia". European Respiratory Journal. European Respiratory Society (ERS): 2001365. doi:10.1183/13993003.01365-2020. ISSN 0903-1936.
  6. Middeldorp, Saskia; Coppens, Michiel; van Haaps, Thijs F.; Foppen, Merijn; Vlaar, Alexander P.; Müller, Marcella C.A.; Bouman, Catherine C.S.; Beenen, Ludo F.M.; Kootte, Ruud S.; Heijmans, Jarom; Smits, Loek P.; Bonta, Peter I.; van Es, Nick (2020-05-05). "Incidence of venous thromboembolism in hospitalized patients with COVID‐19". Journal of Thrombosis and Haemostasis. Wiley. doi:10.1111/jth.14888. ISSN 1538-7933.
  7. Helms, Julie; Tacquard, Charles; Severac, François; Leonard-Lorant, Ian; Ohana, Mickaël; Delabranche, Xavier; Merdji, Hamid; Clere-Jehl, Raphaël; Schenck, Malika; Fagot Gandet, Florence; Fafi-Kremer, Samira; Castelain, Vincent; Schneider, Francis; Grunebaum, Lélia; Anglés-Cano, Eduardo; Sattler, Laurent; Mertes, Paul-Michel; Meziani, Ferhat (2020-05-04). "High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study". Intensive Care Medicine. Springer Science and Business Media LLC. 46 (6): 1089–1098. doi:10.1007/s00134-020-06062-x. ISSN 0342-4642.
  8. Artifoni, Mathieu; Danic, Gwenvael; Gautier, Giovanni; Gicquel, Pascal; Boutoille, David; Raffi, François; Néel, Antoine; Lecomte, Raphaël (2020-05-25). "Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors". Journal of Thrombosis and Thrombolysis. Springer Science and Business Media LLC. 50 (1): 211–216. doi:10.1007/s11239-020-02146-z. ISSN 0929-5305.
  9. Edler, Carolin; Schröder, Ann Sophie; Aepfelbacher, Martin; Fitzek, Antonia; Heinemann, Axel; Heinrich, Fabian; Klein, Anke; Langenwalder, Felicia; Lütgehetmann, Marc; Meißner, Kira; Püschel, Klaus; Schädler, Julia; Steurer, Stefan; Mushumba, Herbert; Sperhake, Jan-Peter (2020-06-04). "Dying with SARS-CoV-2 infection—an autopsy study of the first consecutive 80 cases in Hamburg, Germany". International Journal of Legal Medicine. Springer Science and Business Media LLC. 134 (4): 1275–1284. doi:10.1007/s00414-020-02317-w. ISSN 0937-9827.
  10. Faggiano, Pompilio; Bonelli, Andrea; Paris, Sara; Milesi, Giuseppe; Bisegna, Stefano; Bernardi, Nicola; Curnis, Antonio; Agricola, Eustachio; Maroldi, Roberto (2020). "Acute pulmonary embolism in COVID-19 disease: Preliminary report on seven patients". International Journal of Cardiology. Elsevier BV. 313: 129–131. doi:10.1016/j.ijcard.2020.04.028. ISSN 0167-5273.
  11. Hékimian, Guillaume; Lebreton, Guillaume; Bréchot, Nicolas; Luyt, Charles-Edouard; Schmidt, Matthieu; Combes, Alain (2020-06-02). "Severe pulmonary embolism in COVID-19 patients: a call for increased awareness". Critical Care. Springer Science and Business Media LLC. 24 (1). doi:10.1186/s13054-020-02931-5. ISSN 1364-8535.
  12. Fauvel, Charles; Weizman, Orianne; Trimaille, Antonin; Mika, Delphine; Pommier, Thibaut; Pace, Nathalie; Douair, Amine; Barbin, Eva; Fraix, Antoine; Bouchot, Océane; Benmansour, Othmane; Godeau, Guillaume; Mecheri, Yasmine; Lebourdon, Romane; Yvorel, Cédric; Massin, Michael; Leblon, Tiphaine; Chabbi, Chaima; Cugney, Erwan; Benabou, Léa; Aubry, Matthieu; Chan, Camille; Boufoula, Ines; Barnaud, Clement; Bothorel, Léa; Duceau, Baptiste; Sutter, Willy; Waldmann, Victor; Bonnet, Guillaume; Cohen, Ariel; Pezel, Théo (2020-07-13). "Pulmonary embolism in COVID-19 patients: a French multicentre cohort study". European Heart Journal. Oxford University Press (OUP). doi:10.1093/eurheartj/ehaa500. ISSN 0195-668X.
  13. Poyiadi, Neo; Cormier, Peter; Patel, Parth Y.; Hadied, Mohamad O.; Bhargava, Pallavi; Khanna, Kanika; Nadig, Jeffrey; Keimig, Thomas; Spizarny, David; Reeser, Nicholas; Klochko, Chad; Peterson, Edward L.; Song, Thomas (2020-05-14). "Acute Pulmonary Embolism and COVID-19". Radiology. Radiological Society of North America (RSNA): 201955. doi:10.1148/radiol.2020201955. ISSN 0033-8419.
  14. 14.0 14.1 Stein, Paul D.; Beemath, Afzal; Matta, Fadi; Weg, John G.; Yusen, Roger D.; Hales, Charles A.; Hull, Russell D.; Leeper, Kenneth V.; Sostman, H. Dirk; Tapson, Victor F.; Buckley, John D.; Gottschalk, Alexander; Goodman, Lawrence R.; Wakefied, Thomas W.; Woodard, Pamela K. (2007). "Clinical Characteristics of Patients with Acute Pulmonary Embolism: Data from PIOPED II". The American Journal of Medicine. Elsevier BV. 120 (10): 871–879. doi:10.1016/j.amjmed.2007.03.024. ISSN 0002-9343.
  15. Bikdeli, Behnood; Madhavan, Mahesh V.; Jimenez, David; Chuich, Taylor; Dreyfus, Isaac; Driggin, Elissa; Nigoghossian, Caroline Der; Ageno, Walter; Madjid, Mohammad; Guo, Yutao; Tang, Liang V.; Hu, Yu; Giri, Jay; Cushman, Mary; Quéré, Isabelle; Dimakakos, Evangelos P.; Gibson, C. Michael; Lippi, Giuseppe; Favaloro, Emmanuel J.; Fareed, Jawed; Caprini, Joseph A.; Tafur, Alfonso J.; Burton, John R.; Francese, Dominic P.; Wang, Elizabeth Y.; Falanga, Anna; McLintock, Claire; Hunt, Beverley J.; Spyropoulos, Alex C.; Barnes, Geoffrey D.; Eikelboom, John W.; Weinberg, Ido; Schulman, Sam; Carrier, Marc; Piazza, Gregory; Beckman, Joshua A.; Steg, P. Gabriel; Stone, Gregg W.; Rosenkranz, Stephan; Goldhaber, Samuel Z.; Parikh, Sahil A.; Monreal, Manuel; Krumholz, Harlan M.; Konstantinides, Stavros V.; Weitz, Jeffrey I.; Lip, Gregory Y.H. (2020). "COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up". Journal of the American College of Cardiology. Elsevier BV. 75 (23): 2950–2973. doi:10.1016/j.jacc.2020.04.031. ISSN 0735-1097.
  16. Bikdeli, Behnood; Madhavan, Mahesh V.; Jimenez, David; Chuich, Taylor; Dreyfus, Isaac; Driggin, Elissa; Nigoghossian, Caroline Der; Ageno, Walter; Madjid, Mohammad; Guo, Yutao; Tang, Liang V.; Hu, Yu; Giri, Jay; Cushman, Mary; Quéré, Isabelle; Dimakakos, Evangelos P.; Gibson, C. Michael; Lippi, Giuseppe; Favaloro, Emmanuel J.; Fareed, Jawed; Caprini, Joseph A.; Tafur, Alfonso J.; Burton, John R.; Francese, Dominic P.; Wang, Elizabeth Y.; Falanga, Anna; McLintock, Claire; Hunt, Beverley J.; Spyropoulos, Alex C.; Barnes, Geoffrey D.; Eikelboom, John W.; Weinberg, Ido; Schulman, Sam; Carrier, Marc; Piazza, Gregory; Beckman, Joshua A.; Steg, P. Gabriel; Stone, Gregg W.; Rosenkranz, Stephan; Goldhaber, Samuel Z.; Parikh, Sahil A.; Monreal, Manuel; Krumholz, Harlan M.; Konstantinides, Stavros V.; Weitz, Jeffrey I.; Lip, Gregory Y.H. (2020). "COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up". Journal of the American College of Cardiology. Elsevier BV. 75 (23): 2950–2973. doi:10.1016/j.jacc.2020.04.031. ISSN 0735-1097.