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

doi:10.1016/j.isci.2023.107202

Circulating cellular clusters are associated with thrombotic complications and clinical outcomes in COVID-19

iScience. 2023 Jun 25;26(7):107202. doi: 10.1016/j.isci.2023.107202. eCollection 2023 Jul 21.

Authors

Ander Dorken-Gallastegi¹, Yao Lee², Guansheng Li³, He Li⁴, Leon Naar¹, Xuejin Li⁵, Ting Ye⁶, Elizabeth Van Cott⁷, Rachel Rosovsky⁸, David Gregory⁹, Ronald Tompkins¹⁰, George Karniadakis^{3

11}, Haytham Ma Kaafarani¹, George C Velmahos¹, Jarone Lee¹², Galit H Frydman^{1

2}

Affiliations

¹ Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
² Center for Biomedical Engineering & Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02039, USA.
³ Division of Applied Mathematics, Brown University, Providence, RI 02912, USA.
⁴ Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI 02912, USA.
⁵ Department of Engineering Mechanics, Zhejiang University, Hangzhou, China.
⁶ Information and Computational Mathematics, Ji Lin University, Changchun, China.
⁷ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ School of Engineering, Brown University, Providence, RI 02912, USA.
¹² Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract

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.

Keywords: Cell biology; Health sciences; Immunology; Microbiology.