Biomarkers in Hereditary Angioedema

Abstract

A biomarker is a defined characteristic measured as an indicator of normal, biologic, pathogenic processes, or biological responses to an exposure or intervention. Diagnostic biomarkers are used to detect a disease or a subtype of a disease; monitoring biomarkers are measured serially to assess a medical condition; response biomarkers are used to check biologic response following a medical intervention; predictive biomarkers are used to identify patients who are more likely to respond to a medical intervention; and prognostic biomarkers are used to assess the future likelihood of a clinical event. Although biomarkers have been extensively investigated and validated in many diseases and pathologies, very few are currently useful for the diagnosis, evaluation of disease activity, and treatment of hereditary angioedema (HAE). Pathophysiologic pathways involved in HAE reveal a plethora of molecules from the complement, coagulation, and fibrinolysis systems or from the vascular endothelium, which may serve as biomarkers. The most promising candidates, together with their laboratory readout systems, should be evaluated with regard to their analytical and clinical validity and utility. To be highly specific, such biomarkers should be linked to the pathomechanisms of HAE, particularly the bradykinin-generating cascade. Additionally, major advances in high-throughput omics-based technologies may facilitate the discovery of new candidate biomarkers in the future. This review will cover the existing as well as future potential biomarkers that will support the diagnosis, monitor disease activity, and can be used to assess the efficacy of new avenues of therapy of HAE and other forms of angioedema.

Identification of novel biomarkers to distinguish bradykinin‐mediated angioedema from mast cell‐/histamine‐mediated angioedema

“…In addition, measurement of cleaved high-molecular-weight kininogen (cHK), plasma kallikrein, and activated coagulation factor FXII (FXIIa)-although promisingare laborious. 12,14 Furthermore, laboratory parameters associated with coagulation and fibrinolysis have limited usefulness because of their interpatient variation and lack of specificity. 14 The most promising sources of angioedema biomarkers appear to be the components of the plasma contact system, 16 endothelial cell-related factors, 1 and inflammatory parameters.…”

“…12,14 Furthermore, laboratory parameters associated with coagulation and fibrinolysis have limited usefulness because of their interpatient variation and lack of specificity. 14 The most promising sources of angioedema biomarkers appear to be the components of the plasma contact system, 16 endothelial cell-related factors, 1 and inflammatory parameters. Links between the fibrinolytic system, the contact system, and the coagulation system are discussed in angioedema pathogenesis.…”

“…ACE-AE, there is very limited evidence for biomarkers in general, for example, 6-keto-prostaglandin F1α has been proposed. 13 In HAE, specific parameters such as C1-INH concentration, C1-INH activity, and complement C4 are of limited value as they are permanently lacking or decreased, even in the absence of clinical symptoms 12,14 and do not allow any conclusions to be drawn about an impending attack or occurrence of attacks at all. 15 Bradykinin levels are elevated in HAE and ACE-AE, but not CSU-AE.…”

“…In addition, measurement of cleaved high–molecular‐weight kininogen (cHK), plasma kallikrein, and activated coagulation factor FXII (FXIIa)—although promising—are laborious 12,14 . Furthermore, laboratory parameters associated with coagulation and fibrinolysis have limited usefulness because of their interpatient variation and lack of specificity 14 …”

“…Nevertheless, clinical utility of plasma BK levels is being questioned because of its high sensitivity to pre‐analytical procedures, a very short half‐life, and technically challenging measurement. In addition, measurement of cleaved high–molecular‐weight kininogen (cHK), plasma kallikrein, and activated coagulation factor FXII (FXIIa)—although promising—are laborious 12,14 . Furthermore, laboratory parameters associated with coagulation and fibrinolysis have limited usefulness because of their interpatient variation and lack of specificity 14 …”