Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III

Björkqvist, Jenny; Maat, Steven de; Lewandrowski, Urs; Gennaro, Antonio Di; Oschatz, Chris; Shi, Kai; Nöthen, Markus M.; Drouet, Christian; Braley, Hal; Nolte, Marc W.; Sickmann, Albert; Panousis, Con; Maas, Coen; Renné, Thomas

doi:10.1172/jci77139

Cited by 145 publications

(114 citation statements)

References 77 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…C1-INH deficiency leads to angioedema because it controls contact system activation; in the absence of C1-INH, the contact system releases bradykinin to cause angioedema. Recent evidence supports the notion that F12 mutations also facilitate release of BK [42]. For U-HAE, the mechanism of angioedema formation remains unclear, and no significant data have been reported.…”

Section: Hereditary Angioedemamentioning

confidence: 79%

Novelties in the Diagnosis and Treatment of Angioedema

Cicardi¹,

Suffritti²,

Perego³

et al. 2016

J Investig Allergol Clin Immunol

View full text Add to dashboard Cite

Angioedema is defined as local, noninflammatory, self-limiting edema that is circumscribed owing to increased leakage of plasma from the capillaries located in the deep layers of the skin and the mucosae. Two mediators, histamine and bradykinin, account for most cases of angioedema. Angioedema can occur with wheals as a manifestation of urticaria, and this form is frequently allergic. In the present review, we discuss nonallergic angioedema without wheals, which can be divided into 3 acquired and 4 hereditary forms. Histamine is the mediator in acquired angioedema of unknown etiology (idiopathic histaminergic acquired angioedema), whereas in other forms the main mediator is bradykinin. Angioedema can be caused by C1-inhibitor deficiency (C1-INH-hereditary angioedema and C1-INH-acquired angioedema), mutations in coagulation factor XII (FXII-hereditary angioedema), and treatment with angiotensin-converting enzyme inhibitors (ACEI-acquired angioedema). Etiology remains unclear in acquired angioedema (idiopathic nonhistaminergic acquired angioedema) and in 1 type of hereditary angioedema (hereditary angioedema of unknown origin). Several treatments are licensed for hereditary C1-INH deficiency. Plasma-derived and recombinant C1-INHs, the bradykinin receptor blocker icatibant, and the plasma kallikrein inhibitor ecallantide have been approved for on-demand treatment to reverse angioedema symptoms. Attenuated androgen and plasma-derived C1-INH are approved for prophylaxis. Key words: Angioedema. Bradykinin. Histamine. C1 inhibitor. Coagulation factor XII. Angiotensin-converting enzyme inhibitors. Urticaria. ResumenAngioedema se define como un edema local, autolimitado, no-inflamatorio. Se trata de un edema circunscrito debido a la trasvasación de plasma de los capilares localizados en los sustratos profundos de la piel y de las mucosas. En la mayoría de los casos están implicados dos mediadores, la histamina y la serotonina. Puede manifestarse en forma de habones como en la urticaria de origen alérgico. El angioedema de origen no alérgico es el motivo de esta revisión. Se puede presentar bajo 3 formas adquiridas y 4 formas hereditarias. La histamina es el mediador implicado en el angioedema adquirido de etiología desconocida (angioedema adquirido idiopático histaminérgico). En las otras formas se sospecha que es la serotonina el mediador principal. La etiología del angioedema puede ser identificado en 4 tipos: una deficiencia de C1-inhibidor (C1-INH-angioedema hereditario y C1-INH-angioedema adquirido), mutaciones en el factor XII de coagulación (FXII-angioedema hereditario), tratamiento con inhibidores del enzima convertidor de la angiotensina (ACEi-angioedema adquirido). En uno de los adquiridos (angioedema adquirido idiopático no histaminérgico) y en el hereditario de origen desconocido, no se ha identificado todavía su etiología. Varios tratamientos están aprobados para revertir los síntomas clínicos y se aplican en la deficiencia de angioedema hereditario por déficit de C1-INH: Derivados de plasma y C1-IN...

show abstract

Section: Hereditary Angioedemamentioning

confidence: 79%

Novelties in the Diagnosis and Treatment of Angioedema

Cicardi¹,

Suffritti²,

Perego³

et al. 2016

J Investig Allergol Clin Immunol

View full text Add to dashboard Cite

show abstract

“…We hypothesized that low FXII reduces kallikrein formation and consequently the release of bradykinin, which hinders formation of edema (opposite of hereditary angioedema type III, in which a gain of function in FXII induces formation of edema). 32 In thrombotic mice with low FXII, impaired edema formation would worsen the phenotypic response through an inability to manage intravenous pressure after thrombotic occlusion. Quantitation of edema in the head (measured by the thickness of the edemic dermis in coronal sections of the head) did not provide any information regarding low FXII-altered edema formation (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Heestermans¹,

Salloum-Asfar²,

Salvatori³

et al. 2016

Blood

View full text Add to dashboard Cite

Key Points• Platelets, neutrophils, and coagulation factor XII are implicated as important players in experimental venous thrombosis pathophysiology.• We demonstrate that platelets, but not neutrophils, are critical in spontaneous venous thrombosis, whereas low factor XII aggravates thrombosis.Recently, platelets, neutrophils, and factor XII (FXII) have been implicated as important players in the pathophysiology of venous thrombosis. Their role became evident in mouse models in which surgical handling was used to provoke thrombosis. Inhibiting anticoagulation in mice by using small interfering RNA (siRNA) targeting Serpinc1 and Proc also results in a thrombotic phenotype, which is spontaneous (no additional triggers) and reproducibly results in clots in the large veins of the head and fibrin deposition in the liver. This thrombotic phenotype is fatal but can be fully rescued by thrombin inhibition. The mouse model was used in this study to investigate the role of platelets, neutrophils, and FXII. After administration of siRNAs targeting Serpinc1 and Proc, antibody-mediated depletion of platelets fully abrogated the clinical features as well as microscopic aspects in the head. This was corroborated by strongly reduced fibrin deposition in the liver. Whereas neutrophils were abundant in siRNA-triggered thrombotic lesions, antibody-mediated depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, or thrombus morphology. In addition, absence of circulating neutrophils did not affect quantitative liver fibrin deposition. Remarkably, siRNAmediated depletion of plasma FXII accelerated the onset of the clinical phenotype; mice were affected with more severe thrombotic lesions. To summarize, in this study, onset and severity of the thrombotic phenotype are dependent on the presence of platelets but not circulating neutrophils. Unexpectedly, FXII has a protective effect. This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology. (Blood. 2016;127(21):2630-2637

show abstract

“…Activation of coagulation factor X (FX) by Russell's viper venom and Xase is altered in the presence of O-glycans, 22 as is the sensitivity of coagulation factor XII (FXII) to contact activation, with loss of FXII O-glycans recently implicated in the pathogenesis of hereditary angioedema. 23 Furthermore, murine studies have shown that O-glycans are important for the hemostatic process in vivo, because truncation of O-glycans results in severe bleeding deficits, aberrant angiogenesis, and platelet biogenesis, whereas loss of specific O-glycan sites leads to increased bleeding time and VWF insufficiency. [24][25][26] These examples suggest important functions of O-glycosylation, yet, primarily because of technical limitations, we have little information on where the O-glycans are localized.…”

Section: Introductionmentioning

confidence: 99%

Characterizing the O-glycosylation landscape of human plasma, platelets, and endothelial cells

et al. 2017

View full text Add to dashboard Cite

Key Points• Human platelets, endothelial cells, and plasma proteins are extensively O-glycosylated, with .1123 O-glycosites identified in this study.• O-glycosites can be classified into functional subgroups; one important function includes the protection from proteolytic processing.The hemostatic system comprises platelet aggregation, coagulation, and fibrinolysis, and is critical to the maintenance of vascular integrity. Multiple studies indicate that glycans play important roles in the hemostatic system; however, most investigations have focused on Using an unbiased screen to identify associations between O-glycosites and protein annotations we found that O-glycans were over-represented close (6 15 amino acids) to tandem repeat regions, protease cleavage sites, within propeptides, and located on a select group of protein domains. The importance of O-glycosites in proximity to proteolytic cleavage sites was further supported by in vitro peptide assays demonstrating that proteolysis of key hemostatic proteins can be inhibited by the presence of O-glycans.Collectively, these data illustrate the global properties of native O-glycosylation and provide the requisite roadmap for future biomarker and structure-function studies.

show abstract

Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III

Cited by 145 publications

References 77 publications

Novelties in the Diagnosis and Treatment of Angioedema

Novelties in the Diagnosis and Treatment of Angioedema

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Characterizing the O-glycosylation landscape of human plasma, platelets, and endothelial cells

Contact Info

Product

Resources

About