General pathology · Inflammation
Histamine, serotonin, bradykinin and the plasma protein cascades !
- Mechanism
Histamine from mast cells and bradykinin from plasma make vessels leak within minutes; the clotting, kinin and complement systems are wired together.
Updated 2026-11-01
What it is
Vasoactive amines are stored mediators released in seconds: histamine from mast cells and basophils, serotonin from platelets. Bradykinin comes from the kinin system, one of four linked plasma cascades (kinin, clotting, fibrinolysis, complement) set off by activated factor XII. Knowing which mediator causes a swelling matters: histamine angioedema responds to antihistamines and adrenaline, bradykinin angioedema (hereditary or from ACE inhibitors) does not.
Key facts
- Serotonin is stored in platelet dense granules and enterochromaffin cells; it is mainly a vasoconstrictor, with a minor role in human inflammation.
- C1 inhibitor blocks C1, factor XIIa and kallikrein; when it is missing, bradykinin accumulates.
- Plasmin dissolves fibrin; fibrin split products increase vascular permeability.
- Thrombin activates endothelium and leukocytes through protease-activated receptors, linking coagulation to inflammation.
Step by step
- Triggers degranulate mast cells: IgE cross-linking, C3a and C5a, trauma, cold or heat, some drugs and toxins.
- Histamine acts on H1 receptors: arterioles dilate, venular endothelium contracts and leaks, bronchial muscle contracts.
- Separately, factor XII (Hageman factor) is activated on contact with collagen, basement membrane or activated platelets.
- Factor XIIa converts prekallikrein to kallikrein; kallikrein activates more factor XII, a positive loop.
- Kallikrein cleaves high-molecular-weight kininogen and releases bradykinin: leakage, vasodilation, smooth muscle contraction, pain.
- Factor XIIa also starts the intrinsic clotting pathway; plasmin and kallikrein can cleave complement, linking the four cascades.
- Bradykinin is rapidly degraded by kininase II, the same enzyme as angiotensin-converting enzyme (ACE).
Histamine-mediated vs bradykinin-mediated swelling
| Feature | Histamine (mast cell) | Bradykinin |
|---|---|---|
| Examples | Allergic urticaria and angioedema, anaphylaxis | Hereditary angioedema (C1 inhibitor deficiency), ACE-inhibitor angioedema |
| Hives and itch | Usually present | Absent |
| Time course | Minutes; resolves in hours | Builds over hours; lasts days |
| Response to antihistamines, adrenaline and glucocorticoids | Good | Poor |
| Laboratory clue | Tryptase may rise in anaphylaxis | Low C4 in hereditary angioedema |
Clinical notes
- ACE inhibitors can cause angioedema of the lips, tongue and larynx because bradykinin is not degraded; the drug class is stopped for good.
- Hereditary angioedema causes recurrent swelling without hives, attacks of abdominal pain and risk of laryngeal oedema; treatment targets the bradykinin pathway.
- Carcinoid syndrome (flushing, diarrhoea, right-sided valve disease) reflects serotonin and other amines from neuroendocrine tumours, usually with liver metastases.
Test yourself
Think of the answer, then tap the question to see it.
Why can ACE inhibitors cause angioedema?
ACE is kininase II, which breaks down bradykinin; inhibiting it lets bradykinin build up and increase vascular permeability.
Which laboratory finding supports hereditary angioedema?
Low C4, with a low C1 inhibitor level (type I) or poor C1 inhibitor function (type II).
Which receptor mediates the vascular effects of histamine in inflammation?
The H1 receptor on endothelial and smooth muscle cells.
Related
- Mediators of inflammation: the table to know
- Vascular changes in acute inflammation: vasodilation, leakage, exudate vs transudate
- Arachidonic acid metabolites in inflammation, and the drugs that block them
- Disseminated intravascular coagulation: how consumption causes both clots and bleeding
Related conditions
Elsewhere in DurgiPedia
- Type I hypersensitivity (immediate, IgE)
- Mast cell and basophil
- Complement: three pathways, MAC, regulators
- The coagulation cascade
- Fibrinolysis and natural anticoagulants
- Serotonin (5-hydroxytryptamine)
In Pharmacology
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Hereditary angioedema: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Hives | Rash | Skin Rash | Itchy Skin | MedlinePlus (MedlinePlus, US National Library of Medicine, 2026); 17.5 Inflammation and Fever (OpenStax (Microbiology), 2016).
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Representative model, for educational purposes only.