Persistent complement dysregulation with signs of thromboinflammation in active Long Covid

The study, “Persistent complement dysregulation with signs of thromboinflammation in active Long Covid” provides critical insights into the biological underpinnings of Long Covid by examining biomarkers associated with this condition.

Here’s a detailed summary:

Study Overview:

  • Objective: To identify biomarkers associated with Long Covid by studying the immune response and serum protein levels in COVID-19 patients up to 1 year post-infection.
  • Methods: The study followed 39 healthy controls and 113 COVID-19 patients, including a subset of 40 patients with Long Covid symptoms at the 6-month follow-up. Researchers conducted a proteomic analysis, measuring more than 6500 proteins in serum samples using the SomaScan platform​​.

Key Findings:

  1. Complement Activation in Long Covid: Patients with Long Covid exhibited increased complement activation during the acute phase of the disease, which persisted at the 6-month follow-up. Blood complement levels normalized in Long Covid patients who recovered before the 6-month mark. However, there was an imbalance in the formation of the terminal complement complex (TCC), marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that incorporate into cell membranes. This imbalance suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage​​.
  2. Thromboinflammatory Signature in Long Covid: Long Covid patients showed elevated markers of tissue injury in the blood and a thromboinflammatory signature characterized by markers of endothelial activation such as von Willebrand factor (vWF) and red blood cell lysis. This was accompanied by low antithrombin III levels, indicating increased cleavage by thrombin, a driver of TCC formation. Additionally, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates, especially in cases where Long Covid persisted for 12 months or more​​.
  3. Complement Component 7 (C7) Complexes in Long Covid: The study found significantly reduced serum C7 complexes in patients with 6-month Long Covid at the follow-up, consistent across both mild and severe cases. This contrasted with patients who had recovered from Long Covid, where normal serum levels of C7 complexes were observed. Importantly, total C7 levels were comparable between individuals with and without 6-month Long Covid, suggesting an isolated decrease in C7 complexes specifically associated with active Long Covid​​.

Conclusions and Implications:

  • The study concludes that active Long Covid is characterized by a blood protein signature indicative of increased complement activation and thromboinflammation. Tissue injury in Long Covid may be complement-mediated and could further activate the complement system. The findings highlight the potential of complement activation, driven by antigen–antibody complexes involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system, in the pathology of Long Covid.
  • These insights offer a basis for new diagnostic solutions and support clinical research on complement modulators for patients suffering from Long Covid, providing a new perspective on the biological mechanisms underlying this condition​​.

In summary, this study sheds light on the persisting immune dysregulation in Long Covid, particularly focusing on complement system dysregulation and thromboinflammation, offering potential avenues for diagnosis and therapeutic intervention.

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