In situ pulmonary thrombosis and pulmonary embolus are distinct thrombotic phenotypes in critically ill patients with COVID-19 Acute Respiratory Distress Syndrome
Daniël G. Aynekulu Mersha (Erasmus MC)
Boaz Lopuhaä (Erasmus MC)
Hester A. Gietema (Maastricht University Medical Center, Maastricht University)
Jim Smit (Erasmus MC, Radboud Universiteit Nijmegen, TU Delft - Electrical Engineering, Mathematics and Computer Science)
Anne E. Wind (St. Antonius Hospital)
Anne Marije Hulshof (Maastricht University Medical Center)
Katrijn Daenen (Erasmus MC)
Jessica Khyali (Erasmus MC)
Jan H. von der Thüsen (Erasmus MC)
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Abstract
Background Pulmonary embolism (PE) is thought to originate from distal thrombosis. However, in hyperinflammatory conditions, such as COVID-19, thrombosis in the lung vasculature may occur independently of peripheral thrombosis, denoted as in situ thrombosis (IST). Objectives We hypothesize that IST results from a dysregulated immune response involving both T-helper type 1 (Th1) and non-Th1 cell upregulation and can be distinguished from PE by histologic, serologic, and radiologic features. Methods This study included critically ill patients who succumbed to COVID-19 and from whom pulmonary histopathological examination was obtained. Patients were categorized based on histologic characteristics as either IST (thrombus originating from the vessel wall, with a disorganized structure) or PE (centrally in the vessel, with a layered structure) or as controls (without any pulmonary thrombosis). Inflammation, endothelial activity, and hemostasis biomarkers were measured in blood, and computed tomography scans were analyzed. Results Of 21 included patients, n = 6 were categorized as IST, n = 8 as PE, and n = 7 as controls (those who did not have pulmonary thrombosis). Radiologic features of IST included irregular filling defects along vessel walls in smaller arteries in areas with infiltrates. Patients with IST had higher levels of interleukin [IL]-17, IL-18 and IL-33 than those with PE and controls, indicating upregulation of both Th1 and non-Th1 cell pathways. Conclusion IST and PE are distinct forms of pulmonary thrombosis. IST originates from the pulmonary vessel wall and is characterized by skewing from an effective immune response to upregulation of Th1, Th2, and Th17 cell pathways.
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