## Anaphylatoxins and Their Potency **Key Point:** C5a is the most potent anaphylatoxin generated during complement activation, produced by all three pathways (classical, alternative, and lectin). ### Anaphylatoxin Hierarchy | Component | Potency | Source Pathways | Primary Effects | | --- | --- | --- | --- | | C5a | **Most potent** | All three | Chemotaxis, mast cell degranulation, increased vascular permeability | | C3a | Moderate | All three | Mast cell degranulation, smooth muscle contraction | | C4a | Weak | Classical, Lectin | Minimal anaphylactic activity | | C2a | Negligible | Classical, Lectin | No anaphylactic activity | **High-Yield:** C5a is ~200-fold more potent than C3a in inducing mast cell degranulation and is the primary driver of complement-mediated inflammation. ### Mechanism of C5a Action 1. Binds to C5a receptors (C5aR1 and C5aR2) on mast cells, neutrophils, and endothelial cells 2. Triggers G-protein coupled receptor signaling 3. Causes release of histamine, tryptase, and inflammatory mediators 4. Increases vascular permeability and smooth muscle contraction 5. Promotes neutrophil chemotaxis and activation **Clinical Pearl:** Excessive C5a generation is implicated in sepsis-induced shock, acute respiratory distress syndrome (ARDS), and anaphylaxis. C5a inhibitors (e.g., eculizumab) are used therapeutically in complement-mediated diseases. **Mnemonic:** **C5a = Catastrophic anaphylatoxin** — remember it as the "5-star" inflammatory mediator.
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