Hereditary angioedema: the plasma contact system out of control: reply

Abstract

We thank Drs Loffredo and Marone for their interest in our article and correspondence, which summarizes their impressive scientific contributions to the complex field of vascular biology.In our review, we provide an overview of the role of the plasma contact system, classically seen as part of the coagulation system, in hereditary angioedema [1]. The active role of the contact system in this pathology is evident, as both C1 esterase inhibitor (C1INH) deficiency and gain-of-function mutations in factor XII (FXII) result in hereditary angioedema (HAE). After decades of investigation, it became clear that clinical symptoms of C1INH deficiency are attributable to contact systemdependent bradykinin formation, rather than a complement-related disease mediator [2]. This is supported by positive clinical experience with selective kinin B2 receptor (B2R) antagonism [3], as well as prophylactic selective blockade of plasma kallikrein (PKa) in C1INH deficiency [4]. Together these findings show us that the contact system is very important in C1INH-HAE.For other types of HAE with normal C1INH activity that have been identified more recently, disease mediators are sometimes less clear. Biochemical studies by us and others have shown that mutations in the gene that encodes FXII change protein glycosylation, which lowers the threshold for binding to triggering polyanions [5]. Furthermore, several of these mutations introduce novel cleavage sites that are sensitive to plasmin. Truncation of pathogenic mutant FXII by plasmin amplifies its capacity for enzymatic activation in solution [6]. The former paper shows in vivo in mouse models that the pathogenic prop-erties of mutant FXII are dependent on prekallikrein activation [5]. The latter paper demonstrates that induction of plasminogen activation in FXII-HAE patient plasma provokes an 'explosion' of bradykinin production [6]. However, neither paper definitively demonstrates that bradykinin is a critical disease mediator in human FXII-HAE patients during a real-world angioedema attack. Fortunately, recent clinical studies have demonstrated that this is most probably the case: both infusion of additional C1INH and B2R inhibition are therapeutic in FXII-HAE patients [7].In our review, we propose that plasmin makes a significant contribution to bradykinin C1INH-HAE and FXII-HAE; firstly, levels of plasmin-a2-antiplasmin complexes are elevated during swelling attacks [8,9]. Secondly, there is a growing body of biochemical evidence for a role of plasmin as activator of the contact system [6,10,11] More convincingly, there good clinical experience with tranexamic acid as a maintenance therapy in both forms of HAE [7,12,13], and even in patients with (H)AE of unknown origin [14]. This may be explained by our biochemical findings that show that tranexamic acid blocks FXII activation by plasmin [6].The identification of a mutation in the plasminogen (PLG) gene in families with HAE from multiple countries gives rise to the idea that plasmin is an active contributor to bradykinin production [...

A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain

“…4,8-10 rarely, HAE occurs in individuals with normal C1-INH activity, and has been linked to mutations in other proteins, FXII, plasminogen, and angiopoietin 1. 9,10,14,15 Lysine or arginine replacements for Thr 309 in the FXII proline-rich region have been identified in several families with HAE and normal C1-INH. [16][17][18][19][20] Trypsin-like enzymes including coagulation and fibrinolytic proteases cleave substrates after lysine or arginine.…”

“…3,4,6,7 Excessive bradykinin formation due to accelerated activation or dysregulation of the KKS contributes to a range of pathologies including angioedema (rapid soft tissue swelling). 4,7,8 In hereditary angioedema (HAE), which affects ;1 in 50 000 individuals, 9,10 patients experience episodic swelling of the face, airway, limbs, or gastrointestinal tract. Consistent with a role for bradykinin, kallikrein inhibitors reduce the frequency and severity of angioedema in HAE patients.…”

“…[11][12][13] HAE is usually caused by reduced plasma activity of the serpin C1 inhibitor (C1-INH), the main regulator of kallikrein and aFXIIa. [8][9][10] However, HAE does occur in patients with normal C1-INH activity. 14,15 In some, Thr 309 in FXII is replaced with lysine or arginine.…”

Polyphosphates and Complement Activation

“…C1-esterase inhibitor (C1-INH) is a serine protease inhibitor that highlights the coordinated regulation of coagulation and complement (10). In coagulation, C1-INH interferes with the proteolytic activities of factor XIa, factor XIIa, and kallikrein, suppressing the contact/intrinsic pathways of coagulation and inflammation.…”

“…In this report, I review the complement system, highlighting some key mechanisms by which it is regulated, and how it interfaces with coagulation [Readers are referred to excellent reviews of the coagulation cascade (7–10)]. I then focus on recently uncovered insights into the role of the polyanion polyphosphate (polyP)—known to promote coagulation—in dampening complement activation.…”