OC 22.3 - Monocytes and Macrophages Promote Increased Tissue Factor/Factor VIIa-Dependent Procoagulant Activity in Response to the SARS-CoV-2 Spike Protein

Background: Venous thromboembolism (VTE) is a high-incidence complication of severe SARS-CoV-2-associated COVID-19. The precise mechanisms by which SARS-CoV-2 leads to hypercoagulability and VTE are not fully understood but are thought to be multifactorial. Recently, abnormal tissue factor expression has been linked to thromboembolic events in patients with SARS-CoV-2-associated COVID-19. Monocytes and macrophages are the predominant source of tissue factor in peripheral circulation, which suggests a potential pathomechanistic interplay between SARS-CoV-2 and the monocyte-macrophage axis. However, the link between monocytes and macrophages and the thromboembolic risk associated with COVID-19 is largely unaddressed.

Aims: In this study, we investigated changes in monocyte/macrophage procoagulant activity in response to the SARS-CoV-2 spike protein.

Methods: Immortalised human-derived monocytes and differentiated macrophages were treated with the SARS-CoV-2 spike protein, and changes in monocyte/macrophage procoagulant activity were assessed using biochemical and haematological assays.

Results: The ancestral Wuhan-Hu-1 SARS-CoV-2 spike protein induced time- and concentration-dependent increases in monocyte/macrophage procoagulant activity, characterised by a significant reduction in the recalcified clotting time of human plasma (p < 0.001). When treated with the spike proteins of Delta (B.1.617.2) or Omicron (B.1.1.529), monocyte/macrophage procoagulant activity correlated with the severity of the SARS-CoV-2 variant of concern. Furthermore, spike protein-induced procoagulant activity was shown to require extrinsic coagulation factors; in particular, recalcified clotting times were significantly affected by deficiencies in tissue factor-factor VIIa complexes (p < 0.001). Interestingly, preventing the interaction of the SARS-CoV-2 spike protein with ACE2 – the SARS-CoV-2 receptor – attenuated monocyte/macrophage procoagulant activity, suggesting a possible role for ACE2 in procoagulant signalling.

Conclusion(s): Collectively, our data suggests that the SARS-CoV-2 spike protein promotes tissue factor/factor VIIa-dependent procoagulant activity in monocytes and macrophages. Investigations are on-going to further understand the pathophysiological interplay between SARS-CoV-2 and the monocyte-macrophage axis in patients with COVID-19.