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Complement and platelets: prothrombotic cell activation requires membrane attack complex-induced release of danger
Marco Mannes1, Veronika Pechtl2, Susanne Hafner2
1Institute of Clinical and Experimental Trauma Immunology, University Hospital of Ulm, Ulm, Germany.
Blood Advances
|July 10, 2023
Summary
Complement activation causes blood clots in PNH and aHUS. Blocking the terminal complement pathway prevents clots by stopping cell lysis and ADP release, explaining why anticomplement therapy is effective.
Area of Science:
- Immunology
- Hematology
- Pathophysiology
Background:
- Complement activation drives thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).
- Current anticomplement therapies prevent thrombotic events, but the precise mechanisms are unclear.
- Anticoagulation and antiplatelet therapies are largely ineffective against complement-driven thrombosis.
Purpose of the Study:
- To elucidate the mechanisms by which complement activation leads to thrombotic events in PNH and aHUS.
- To investigate the role of complement components and pathways in platelet activation and thrombosis.
- To determine why anticomplement therapy is effective in preventing thrombosis in these diseases.
Main Methods:
- In vitro studies using whole human blood to assess complement-mediated platelet activation.
- Functional assays measuring platelet response to complement anaphylatoxins (C3a, C5a) and complement activation products.
- In vivo validation using a rat model of mismatched erythrocyte transfusion, complement inhibition (OmCI), and cobra venom factor.
Main Results:
- Complement-mediated hemolysis in whole blood induced platelet activation, similar to adenosine 5'-diphosphate (ADP).
- Blocking complement components C3 or C5 abolished platelet activation.
- Platelets did not respond to anaphylatoxins C3a and C5a; prothrombotic activation occurred only with membrane attack complex (MAC)-mediated cytolysis.
- ADP receptor antagonists inhibited platelet activation even during full complement activation.
- In vivo studies confirmed that thrombosis only occurred when MAC-mediated cytolysis happened.
Conclusions:
- Complement activation induces substantial prothrombotic cell activation only when the terminal pathway culminates in MAC-mediated release of intracellular ADP.
- This mechanism explains the efficacy of anticomplement therapy in preventing thromboembolism without impairing normal hemostasis.
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