COVID-19-associated pulmonary embolism

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 whole world.
• Various case reports and case series have suggested hypercoagulability to be one of the cause 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.

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. Elevation of d-dimers Elevation of C-reactive protein Elevated factor VIII and von Willebrand factor A decrease in Antithrombin level Increased fibrinogen levels

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

Risk Factors

Multivariate analysis showed following risk factors that predispose a patient of COVID-19 to 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

Diagnosis

History and Symptoms

• Pulmonary embolism can present with no symptoms to shock and even sudden cardiac arrest.
• The most common symptoms that were observed in Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) trial include:
  • 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%)

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

CTPA & Ventilation/Perfusion Scan

• Prompt diagnosis of PE in COVID-19 patient is difficult in this regard that various symptoms of COVID-19 overlap with that of pulmonary embolism. American Society of Hematology provides the following guidelines 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

• 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. In 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.