The Search for Biomarkers in Hereditary Angioedema

Kaplan, Allen P.; Maas, Coen

doi:10.3389/fmed.2017.00206

Cited by 41 publications

(49 citation statements)

References 53 publications

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“…Comprehensive studies have identified BK as the principal mediator of vascular leakage in C1-INH-HAE-related swelling attacks ( 10 , 62 ) Circulating levels of BK, markers of endothelial activation, prothrombin fragments, D-dimer ( 63 ), cytokines (e.g., TNF-α and IL-8), as well as neutrophil count and neutrophil-derived factors (e.g., elastase, myeloperoxidase, pentraxin 3) ( 64 ) are increased during attacks compared with symptom-free periods in C1-INH-HAE patients. By contrast, we found that sPLA 2 activity is consistently decreased during attacks and does not correlate with canonical biomarkers of angioedema severity (i.e., cleaved HK) ( 65 ). Whatever the mechanism(s), sPLA 2 is the first mediators so far identified which shows opposite behavior during clinical remission (i.e., increase) and angioedema attacks (i.e., reduction).…”

Section: Discussioncontrasting

confidence: 67%

Secreted Phospholipases A2 in Hereditary Angioedema With C1-Inhibitor Deficiency

et al. 2018

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BackgroundHereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s).ObjectiveWe sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE.MethodssPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay.ResultsPlasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro.ConclusionsPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets.

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Section: Discussioncontrasting

confidence: 67%

Secreted Phospholipases A2 in Hereditary Angioedema With C1-Inhibitor Deficiency

et al. 2018

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“…The present data suggest that C1-INH deficiency does not make the contact system unstable, but rather makes it hypersensitive to plasmin. The place of fibrinolysis as a trigger in kinin-mediated angioedema states remains to be investigated in detail; it has been noted that plasmin can activate FXII in the absence of a contact system-surface ( 38 , 46 ). Tranexamic acid was predictably effective in a subtype of HAE due to a mutation in FXII, although the series is small ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency

et al. 2018

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Multiple pathways have been proposed to generate bradykinin (BK)-related peptides from blood. We applied various forms of activation to fresh blood obtained from 10 healthy subjects or 10 patients with hereditary angioedema (HAE-1 or −2 only) to investigate kinin formation. An enzyme immunoassay for BK was applied to extracts of citrated blood incubated at 37°C under gentle agitation for 0–2 h in the presence of activators and/or inhibitory agents. Biologically active kinins in extracts were corroborated by c-Fos accumulation in HEK 293a cells that express either recombinant human B2 or B1 receptors (B2R, B1R). Biological evidence of HAE diagnostic and blood cell activation was also obtained. The angiotensin converting enzyme inhibitor enalaprilat, without any effect per se, increased immunoreactive BK (iBK) concentration under active stimulation of blood. Tissue kallikrein (KLK-1) and Kontact-APTT, a particulate material that activates the contact system, rapidly (5 min) and intensely (>100 ng/mL) induced similar iBK generation in the blood of control or HAE subjects. Tissue plasminogen activator (tPA) slowly (≥1 h) induced iBK generation in control blood, but more rapidly and intensely so in that of HAE patients. Effects of biotechnological inhibitors indicate that tPA recruits factor XIIa (FXIIa) and plasma kallikrein to generate iBK. KLK-1, independent of the contact system, is the only stimulus leading to an inconsistent B1R stimulation. Stimulating neutrophils or platelets did not generate iBK. In the HAE patients observed during remission, iBK formation capability coupled to B2R stimulation appears largely intact. However, a selective hypersensitivity to tPA in the blood of HAE patients suggests a role of plasmin-activated FXIIa in the development of attacks. Proposed pathways of kinin formation dependent on blood cell activation were not corroborated.

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“…The diagnostic impasses described above highlight the absence of biological markers to identify the key mediator of AE. Different diagnostic strategies have been proposed such as: 21,[62][63][64][65] • For MC-AE: Tryptase, D-Dimers, urinary histamine and methylhistamine excretion; • For BK-AE: VE-Cadherin, HWK cleavage, plasma kallikrein activity, C4a.…”

Section: Challenging Idiopathic Non-mc-ae (Inmc-ae)mentioning

confidence: 99%

<p>Idiopathic Angioedema: Current Challenges</p>

Belbézier¹,

Bocquet²,

Bouillet³

2020

JAA

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The etiological diagnosis of isolated recurrent angioedema poses problems because it must often be done urgently. Angioedema secondary to nonspecific mast cell activation (MC-AE) is the most frequent form and is usually mild. Bradykinin mediated angioedema (BK-AE) is rarer but potentially fatal in the absence of the correct treatment. Few biological markers exist. The C1-inhibitor (C1-inh) functional assay can exclude AE due to C1-inh deficiency. Genetic diagnoses of hereditary AE due to abnormal C1-inh AE have progressed with four currently known mutations. However, determining the physiopathological mechanism leading to some isolated AE cases is sometimes very difficult. In such cases, therapeutic tests are then the only solution: antihistamines at high doses and omalizumab for suspected MC-AE, icatibant for suspected AE-BK. Identifying new markers would be a great help.

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The Search for Biomarkers in Hereditary Angioedema

Cited by 41 publications

References 53 publications

Secreted Phospholipases A2 in Hereditary Angioedema With C1-Inhibitor Deficiency

Secreted Phospholipases A2 in Hereditary Angioedema With C1-Inhibitor Deficiency

Comparing Pathways of Bradykinin Formation in Whole Blood From Healthy Volunteers and Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency

<p>Idiopathic Angioedema: Current Challenges</p>

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