# Thrombin Generation Induced by Complement Component C1q Interaction With the Receptor for the Globular Head of C1q on Adventitial Fibroblasts and Vascular Smooth Muscle Cells

## TL;DR

This study shows that C1q interaction with gC1qR on vascular cells increases thrombin generation, linking inflammation and blood clotting.

## Contribution

The study demonstrates that C1q-gC1qR interaction activates extrinsic coagulation via TF expression on vascular cells.

## Key findings

- C1q exposure increases TF expression on vascular cells, promoting coagulation.
- TF up-regulation leads to thrombin generation and altered Akt/p-Akt signaling.
- These findings connect innate inflammation with enhanced thrombotic activity.

## Abstract

Heightened inflammatory and thrombotic processes are common hallmarks of vascular diseases. The interaction between these two processes remains unclear and a better understanding of these links can allow for the design of more effective treatment options. Activation of complement component 1 (C1) leads to the initiation of the classical arm of the complement cascade, availability of plasma C1q, and the potential association of C1q and receptors for C1q. The association of C1q and gC1qR, the receptor for the globular head of C1q, is notable and has been associated with a wide range of disturbed physiological processes. We have recently shown that when this interaction occurs on vascular wall cells, including adventitial fibroblasts and vascular smooth muscle cells, there is a significant up‐regulation of tissue factor (TF) expression. However, whether or not this TF is biologically active and can facilitate extrinsic coagulation activation remains unknown. We hypothesized that TF expressed via gC1qR‐C1q association would support the progression of extrinsic coagulation.

We quantified the association of Factor VII/VIIa (FVII/FVIIa) with adventitial fibroblast and vascular smooth muscle cell TF, using colorimetric assays. Further, we observed the formation of Factor Xa and Factor IIa (thrombin), as well as the concentration of intracellular Akt (protein kinase B) and phosphorylated Akt.

Our results indicate that TF expression in response to C1q exposure accelerates zymogen formation within the extrinsic coagulation cascade and alters Akt/p‐Akt expression. Overall, these findings highlight a significant connection between altered innate inflammation and heightened thrombin generation.

Research reported in this publication was supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health under award number R21AI146535. The authors (BG) receive royalties from the sale of monoclonal antibodies against gC1qR clone 60.11. The authors (BG) hold a patent for the development of these antibodies for therapy against cancer and angioedema, respectively (US patent 8,883,153‐B2, “Methods for Prevention and Treatment of Angioedema”). The data that support the findings of this study are available from the corresponding author upon reasonable request.