Antibodies and complement are key drivers of thrombosis

Area of Science:

• Immunology
• Hematology
• Vascular Biology

Background:

• Venous thromboembolism (VTE) is a significant cause of morbidity and mortality, with increasing incidence.
• Clinical associations exist between elevated antibodies and thrombotic events, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To elucidate the role of antibodies in the pathogenesis of thrombosis.
• To identify novel therapeutic targets for antibody-mediated thrombosis.

Main Methods:

• Investigated antibody interactions with FcμR and pIgR under reduced blood flow conditions.
• Assessed endothelial activation, platelet recruitment, and IgG deposition.
• Examined complement activation pathways.
• Validated findings in human venous stasis and COVID-19 models.

Main Results:

• Reduced blood flow facilitates IgM binding to FcμR and pIgR, initiating endothelial activation and platelet recruitment.
• Activated platelets promote antigen- and FcγR-independent IgG deposition, leading to complement activation.
• This antibody-driven prothrombotic cascade is observed in human venous stasis and COVID-19.
• Targeting complement effectively prevents antibody-driven thrombosis.

Conclusions:

• Antibodies are central regulators of thrombosis, distinct from their roles in immunity.
• This mechanism offers a target for thrombosis treatment that spares hemostasis.
• Findings have implications for antibody-based therapies and thrombosis management.