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. These patients in their mid-70s had preexisting medical conditions such as cardiac diseases, hypertension, diabetes, and obesity. These studies highlight the role of hypercoagulability as the main contributor to the fatality in these patients. Various studies have described Virchow's triad to be the main component of the hypercoagulable state in these patients.

Historical Perspective

• In late 2019, a novel coronavirus had been identified in Wuhan, China which has now reached a pandemic state across the whole world.
• In May 2020, various autopsies studies revealed pulmonary embolism to be the common cause of death in COVID-19 infected patients.
• These patients in their mid-70s had preexisting medical conditions such as cardiac diseases, hypertension, diabetes, and obesity.
• Various case reports and case series have suggested hypercoagulability to be one of the causes of death in COVID-19 patients.
• Proposed mechanism of multiple organ dysfunction that occurs in COVID-19 patients are multifactorial but they include a hypercoagulable state with micro and macro-circulatory thrombosis.
• Based on these case reports and case series, various guidelines have been proposed now to initiate anticoagulants in critically ill patients and those who are admitted to the hospital.

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 the 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 in lies with 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	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	Most hospitalized critically ill immobile COVID-19 patients are prone to stasis of blood flow leading to another contributor towards the pathogenesis of pulmonary embolism.
Hypercoagulable state	Various clinical studies have reported different prothrombotic factors in patients who are critically ill and are hospitalized due to COVID-19. These studies report various key lab factors that play an important role in the pathogenesis of pulmonary embolism as mentioned below: Elevation of d-dimers Elevation of C-reactive protein Elevated factor VIII and von Willebrand factor A decrease in Antithrombin level Increased fibrinogen levels

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

• Pulmonary embolism in COVID-19 patients can be sudden and can mimic symptoms of other disorders like pneumonia and ARDS. Therefore it has been suggested there should be a lower threshold of imaging for DVT should be reserved for pulmonary embolism in COVID-19 patients admitted to the ICU setting.
  • Differentiating from heart failure: Acute congestive Heart failure presents in context of previous myocardial infarction,hypertension any other previous co-morbidities. There is usually no history of associated chest pain, hemoptysis or low grade fever. Additionally there will be signs of volume overload e.g, distended jugular vein, peripheral edema, hepatomegaly,pulmonary edema etc present in congestive heart failure patient
  • Differentiating from Pericarditis: Acute pericarditis presents similar to acute pulmonary embolism. However there is history of recent viral infection, underlying disease such as uremia, myocardial infarction and can also occur due to malignancy. There would be ST-segment elevation and PR depression on ECG. The chest pain will be relieved by sitting up and leaning forward.
  • Differentiating from Pneumonia: Studies have shown that pneumonia in COVID-19 patients is often the triggering factor for PE. However there will be consolidation on chest x-ray, ground glass opacities, peribronchial nodules. There is also history of high grade fever and productive cough in bacterial pneumonia.

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.
• 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.
• In the non-ICU settings (in-patient), pulmonary embolism is reported to occur in 3% percent of patients in one study.

Risk Factors

• Multivariate analysis showed the following risk factors that predispose a patient of COVID-19 to pulmonary embolism:

Risk factors for COVID-19 associated pulmonary embolism
Obesity (BMI>30 kg/m2) D-dimers level increasing by 6mg/ml Previous history of pulmonary embolism Respiratory tract infection Bedridden patient Genetic predisposition to a hypercoagulable state Fever Diarrhea Sepsis Liver Injury CKD COPD Heart Failure Malignancy

Natural History,Complications and Prognosis

• Pulmonary embolism in critically ill patients of COVID-19 is a frequent finding.
• It can lead to the development of cardiogenic shock, sudden cardiac arrest and pulmonary hypertension if developed chronically.
• There has been various investigational and treatment approach to treat the hypercoagulability leading to these complications in COVID-19 patients.
• Patients that are at risk of pulmonary embolism such as those with deep venous thrombosis are advised to take oral anticoagulants.
• Studies show that there is high cumulative incidence of PE in COVID-19 patients which suggests more frequent use of contrast medium on CT for the evaluation of COVID-19 patients.

Complications

• Various complications have been reported ranging from acute right heart failure and sudden cardiac arrest due to pulmonary embolism in COVID-19 patients. The following complications have been frequently reported in various case reports and case series:
  • Acute heart failure
  • Atrial flutter
  • Pulseless electrical activity
  • Sudden Cardiac Arrest

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

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 can present with no symptoms to shock and even sudden cardiac arrest.
• The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) trial observed the following most common symptoms:
  • 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.

General

• Tachypnea (>20/min)
• Tachycardia (>100/min)
• Diaphoresis
• Cyanosis
• Temperature > 38.5oC (>101.3oF)

Cardiac examination

• Increased P2
• Right ventricular lift
• Jugular venous distension

Lung examination

• Rales (crackles)
• Wheezes
• Rhonchi
• Decreased breath sounds
• Pleural friction rub

DVT signs

• Calf or thigh
• Calf and thigh

Laboratory findings

• Lab findings of different case studies of patients having pulmonary embolism due to COVID-19 are given as
  • Elevated d-dimers
  • Elevated prothrombin time
  • Elevated CRP
  • Elevated Cardiac biomarkers
  • High fibrinogen
  • Mild thrombocytopenia or thrombocytosis
  • Platelet count can be normal

Imaging studies

Chest-X ray

• Chest radiograph is not used as a primarily diagnostic test in pulmonary embolism patients.
• It is neither sensitive and nor specific.
• Chest-X ray is used to rule out other conditions that can mimic symptoms of pulmonary embolism such as bacterial pneumonia ,cardiogenic cause of dyspnea and pneumothorax.

CTPA & Ventilation Perfusion Scan

• The prompt diagnosis of pulmonary embolism in COVID-19 patient is difficult as various symptoms of COVID-19 overlap with that of pulmonary embolism.
• Following are the guidelines provided by American Society of Hematology regarding the diagnosis of pulmonary embolism:
  • Normal d-dimers level in a patient with low to moderate pretest probability is sufficient to rule out the diagnosis of PE. D-dimers level is usually elevated in COVID-19 patients. This is not applicable to a patient with a high pretest probability.
  • Inpatient with suspected PE with symptoms like hypotension, tachycardia, and sudden drop in oxygen saturation with a high pretest probability of PE, computed tomography with pulmonary angiography is used for the diagnosis. Contraindication to the use of CTPA warrants investigation with ventilation/perfusion scan.

Right-sided segmental and subsegmental pulmonary arterial filling defects (yellow arrows) in keeping with acute distal pulmonary emboli. Source: Dr Gianluca Martinellihttps://radiopaedia.org/cases/76817

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: 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	Full dose anti-coagulation is appropriate for diagnosed pulmonary embolism. Fibrinolytic therapy is usually started unless there is a contraindication. e.g, massive PE, acute stroke, and acute myocardial infarction.
Outpatient treatment	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.

Prevention

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.