Circulating cellular clusters are associated with thrombotic complications and clinical outcomes in COVID-19
Ander Dorken-Gallastegi,
Yao Lee,
Guansheng Li,
He Li,
Leon Naar,
Xuejin Li,
Ting Ye,
Elizabeth Van Cott,
Rachel Rosovsky,
David Gregory,
Ronald Tompkins,
George Karniadakis,
Haytham MA. Kaafarani,
George C. Velmahos,
Jarone Lee,
Galit H. Frydman
Affiliations
Ander Dorken-Gallastegi
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
Yao Lee
Center for Biomedical Engineering & Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02039, USA
Guansheng Li
Division of Applied Mathematics, Brown University, Providence, RI 02912, USA
He Li
Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI 02912, USA
Leon Naar
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
Xuejin Li
Department of Engineering Mechanics, Zhejiang University, Hangzhou, China
Ting Ye
Information and Computational Mathematics, Ji Lin University, Changchun, China
Elizabeth Van Cott
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Rachel Rosovsky
Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
David Gregory
Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA
Ronald Tompkins
Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
George Karniadakis
Division of Applied Mathematics, Brown University, Providence, RI 02912, USA; School of Engineering, Brown University, Providence, RI 02912, USA
Haytham MA. Kaafarani
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
George C. Velmahos
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
Jarone Lee
Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Galit H. Frydman
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Biomedical Engineering & Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02039, USA; Corresponding author
Summary: We sought to study the role of circulating cellular clusters (CCC) –such as circulating leukocyte clusters (CLCs), platelet-leukocyte aggregates (PLA), and platelet-erythrocyte aggregates (PEA)– in the immunothrombotic state induced by COVID-19. Forty-six blood samples from 37 COVID-19 patients and 12 samples from healthy controls were analyzed with imaging flow cytometry. Patients with COVID-19 had significantly higher levels of PEAs (p value<0.001) and PLAs (p value = 0.015) compared to healthy controls. Among COVID-19 patients, CLCs were correlated with thrombotic complications (p value = 0.016), vasopressor need (p value = 0.033), acute kidney injury (p value = 0.027), and pneumonia (p value = 0.036), whereas PEAs were associated with positive bacterial cultures (p value = 0.033). In predictive in silico simulations, CLCs were more likely to result in microcirculatory obstruction at low flow velocities (≤1 mm/s) and at higher branching angles. Further studies on the cellular component of hyperinflammatory prothrombotic states may lead to the identification of novel biomarkers and drug targets for inflammation-related thrombosis.
