Pathophysiology

Hereditary Angioedema (HAE) patients have a defect in the gene that controls the plasma protein C1-inhibitor. The genetic defect results in production of either inadequate or non-functioning C1-inhibitor protein. The primary biological role of C1-inhibitor is to regulate activation of the complement system, the contact system, and the fibrinolytic system.

  • Most HAE physician/researchers believe that there is sufficient evidence to conclude the long-standing debate over which peptide is the primary mediator of HAE attacks–C2 kinin or bradykinin. In vitro studies and an in-depth analysis of C1-inhibitor deficient mice pointed to bradykinin. (1,2) These findings are buttressed by results from two late stage human clinical trials that affirmed a B2 bradykinin receptor antagonist’s clinically significant impact in attenuating swelling associated with acute HAE attacks.

    Accordingly, the hypothesized mechanism for initiation of an angioedema attack begins with trauma, infection, febrile illness and other unknown factors that lead to activation of the complement, contact, and/or fibrinolytic systems. (3) This leads to consumption of C1-inhibitor via complex formation with C1r, C1s, MASP’s, factor X11a, kallikrein, tissue plasminogen activator, and/or plasmin.3 Depletion of C1-inhibitor results in complete deregulation of the complement and contact systems with decreasing levels of C4 and C2, and the generation of bradykinin. (3)

    The specific process that produces bradykinin begins with contact system activation in which coagulation factor XII and pre-kallikrein are proteolytically activated into factor XIIa and kallikrein respectively. Kallikrein then cleaves high molecular weight kininogen (it is important to note that high molecular weight kininogen circulates in complex with pre-kallikrein) and, in turn releases bradykinin.4 Bradykinin binds to B2 bradykinin receptors on the endothelial cells and causes an increase in vascular permeability that results in edema. (4)

    (1) Cugno M, et. al. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol. 2003 Mar;3(3):311-7
    (2) Han ED, et. al. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest. 2002 Apr109(8):1057-63
    (3) ADavis III AE. The pathophysiology of hereditary angioedema. Clinical Immunology. 2005;114(3)
    (4) Zuraw BL, Current and future therapy for hereditary angioedema. Clinical Irmunology. 2005;114(l3)

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