Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema

J Allergy Clin Immunol. 2008 Apr;121(4):969-75.e2. doi: 10.1016/j.jaci.2008.01.071.


Background: Although bradykinin is known to play a major role in the pathophysiology of hereditary and angiotensin-converting enzyme inhibitor (ACEi)-induced angioedema, other factors acting as triggers or enhancers are likely important as well.

Objective: We hypothesized that fibrinogen might contribute to ACEi-induced angioedema (eg, through direct actions on vascular tone).

Methods: Plasma levels of fibrinogen were determined in 59 patients with acute angioedema. Vascular activity of human and bovine fibrinogen and its effects on bradykinin-induced vasodilation and phosphorylation of vasodilator-stimulated phosphoprotein were investigated in small (0.8-1.4 mm in diameter) porcine coronary artery and human internal thoracic artery (ITA) segments.

Results: In patients with ACEi-induced angioedema, fibrinogen levels (481 +/- 22 mg/dL, n = 39) were significantly higher than in patients with idiopathic angioedema (302 +/- 15 mg/dL, P < .001). Fibrinogen (1-15 mumol/L) induced a concentration-dependent vasodilation in preconstricted small porcine coronary arteries (n = 13), reaching a maximum vasodilator effect of 70% +/- 4.7%. Likewise, fibrinogen induced a 52.1% +/- 9.1% (n = 7) vasodilation in ITA rings. Fibrinogen vasorelaxations were completely inhibited by abciximab and diminished by endothelial denudation and treatment with the nitric oxide synthase inhibitor L-nitroargininemethylester and glibenclamide (P < .01). Importantly, fibrinogen increased the vasodilator potency of bradykinin by 10-fold (P < .0001) and increased bradykinin-induced vasodilator-stimulated phosphoprotein phosphorylation (P < .01).

Conclusion: The increase of plasma fibrinogen levels, its vasodilator activity in human ITAs, and the potentiation of bradykinin-induced vasodilation suggest that fibrinogen might contribute to the pathophysiology of ACEi-induced angioedema. Thus acute-phase proteins, such as fibrinogen, might be viewed as risk factors for bradykinin-induced angioedema.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angioedema / chemically induced
  • Angioedema / metabolism*
  • Angioedema / physiopathology*
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Bradykinin / blood
  • Bradykinin / toxicity*
  • Cattle
  • Coronary Vessels / drug effects
  • Coronary Vessels / physiology
  • Female
  • Fibrinogen / physiology*
  • Humans
  • Male
  • Middle Aged
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Organ Culture Techniques
  • Recurrence
  • Swine
  • Thoracic Arteries / drug effects
  • Thoracic Arteries / physiology
  • Vasodilation / drug effects
  • Vasodilation / physiology
  • Vasodilator Agents / blood
  • Vasodilator Agents / toxicity*


  • Angiotensin-Converting Enzyme Inhibitors
  • Vasodilator Agents
  • Fibrinogen
  • Bradykinin