-
Allergology International : Official... Jul 2023Hereditary angioedema (HAE) is a rare disorder characterized by cutaneous and submucosal swelling caused mostly by excessive local bradykinin production. Bradykinin is a... (Review)
Review
Hereditary angioedema (HAE) is a rare disorder characterized by cutaneous and submucosal swelling caused mostly by excessive local bradykinin production. Bradykinin is a vasoactive peptide generated by the limited proteolysis of high molecular weight kininogen (HMWK) by plasma kallikrein via the contact activation system. The contact activation system occurs not only in solution but also on the cell surface. Factor XII (FXII), prekallikrein, and HMWK are assembled on the endothelial cell surface via several proteins, including a trimer of a receptor for globular C1q domain in a Zn-dependent manner, and the reciprocal activation on the cell surface is believed to be physiologically important in vivo. Thus, the contact activation system leads to the activation of coagulation, complement, inflammation, and fibrinolysis. C1-inhibitor (C1-INH) is a plasma protease inhibitor that is a member of the serpin family. It mainly inhibits activated FXII (FXIIa), plasma kallikrein, and C1s. C1-INH hereditary deficiency induces HAE (HAE-C1-INH) due to excessive bradykinin production via the incomplete inhibition of plasma kallikrein and FXIIa through the low C1-INH level. HAE is also observed in patients with normal C1-INH (HAEnCI) who carry pathogenic variants in genes of factor XII, plasminogen, angiopoietin 1, kininogen, myoferlin, and heparan sulfate 3-O-sulfotransferase 6, which are associated with bradykinin production and/or vascular permeability. HAE-causing pathways triggered by pathogenic variants in patients with HAE-C1-INH and HAEnCI are reviewed and discussed.
Topics: Humans; Angioedemas, Hereditary; Factor XII; Bradykinin; Plasma Kallikrein; Kininogen, High-Molecular-Weight; Complement C1 Inhibitor Protein; Molecular Biology
PubMed: 37169642
DOI: 10.1016/j.alit.2023.04.004 -
Blood Feb 2020
Topics: Kallikreins; Plasma Kallikrein; Prekallikrein; Proteolysis
PubMed: 32078685
DOI: 10.1182/blood.2019004339 -
Drugs Nov 2019Lanadelumab (Takhzyro™), a first-in-class fully human monoclonal antibody against plasma kallikrein, has been approved in several countries, including Australia,... (Review)
Review
Lanadelumab (Takhzyro™), a first-in-class fully human monoclonal antibody against plasma kallikrein, has been approved in several countries, including Australia, Canada, those of the EU, Switzerland and the USA, for the prevention of hereditary angioedema (HAE) attacks in patients aged ≥ 12 years. Subcutaneous lanadelumab significantly reduced HAE attack rates relative to placebo in the pivotal HELP trial. The clinical benefits of lanadelumab were seen regardless of prior long-term prophylaxis use, baseline disease activity, sex or body mass index. Lanadelumab therapy was associated with clinically meaningful improvements in HAE-specific quality of life. Lanadelumab was generally well tolerated. The most common adverse events with lanadelumab were injection-site reactions, which were generally mild and transient. Lanadelumab has a low potential for immunogenicity. It offers the convenience of self-administered subcutaneous injections once every 2 weeks (starting dosage). Currently available data indicate that lanadelumab is an effective, well-tolerated, novel prophylactic option for patients with HAE aged ≥ 12 years.
Topics: Angioedemas, Hereditary; Antibodies, Monoclonal, Humanized; Humans; Plasma Kallikrein
PubMed: 31560114
DOI: 10.1007/s40265-019-01206-w -
Frontiers in Immunology 2019Factor XII (FXII) is the zymogen of serine protease, factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a... (Review)
Review
Factor XII (FXII) is the zymogen of serine protease, factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a promising target to treat or prevent thrombosis without creating a hemostatic defect. FXII and plasma prekallikrein reciprocally activate each other and result in liberation of bradykinin. Due to its unique structure among coagulation factors, FXII exerts mitogenic activity in endothelial and smooth muscle cells, indicating that zymogen FXII has activities independent of its protease function. A growing body of evidence has revealed that both FXII and FXIIa upregulate neutrophil functions, contribute to macrophage polarization and induce T-cell differentiation. , these signaling activities contribute to host defense against pathogens, mediate the development of neuroinflammation, influence wound repair and may facilitate cancer maintenance and progression. Here, we review the roles of FXII in innate immunity as they relate to non-sterile and sterile immune responses.
Topics: Animals; Blood Coagulation; Bradykinin; Disease Susceptibility; Extracellular Traps; Factor XII; Humans; Immunity, Innate; Immunomodulation; Neutrophils; Plasma Kallikrein; Wound Healing
PubMed: 31507606
DOI: 10.3389/fimmu.2019.02011 -
Journal of Thrombosis and Haemostasis :... Jan 2016The contact activation system (CAS) and kallikrein/kinin system (KKS) are older recognized biochemical pathways that include several proteins that skirt the fringes of... (Review)
Review
The contact activation system (CAS) and kallikrein/kinin system (KKS) are older recognized biochemical pathways that include several proteins that skirt the fringes of the blood coagulation, fibrinolytic, complement and renin-angiotensin fields. These proteins initially were proposed as part of the hemostatic pathways because their deficiencies are associated with prolonged clinical assays. However, the absence of bleeding states with deficiencies of factor XII (FXII), prekallikrein (PK) and high-molecular-weight kininogen indicates that the CAS and KKS do not contribute to hemostasis. Since the discovery of the Hageman factor 60 years ago much has been learned about the biochemistry, cell biology and animal physiology of these proteins. The CAS is a pathophysiologic surface defense mechanism against foreign proteins, organisms and artificial materials. The KKS is an inflammatory response mechanism. Targeting their activation through FXIIa or plasma kallikrein inhibition when blood interacts with the artificial surfaces of modern interventional medicine or in acute attacks of hereditary angioedema restores vascular homeostasis. FXII/FXIIa and products that arise with PK deficiency also offer novel ways to reduce arterial and venous thrombosis without an effect on hemostasis. In summary, there is revived interest in the CAS and KKS due to better understanding of their activities. The new appreciation of these systems will lead to several new therapies for a variety of medical disorders.
Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Bradykinin; Factor XII; Factor XIIa; Hemostasis; Homeostasis; Humans; Inflammation; Kallikrein-Kinin System; Kininogen, High-Molecular-Weight; Mice; Plasma Kallikrein; Prekallikrein; Receptors, Bradykinin; Thrombosis
PubMed: 26565070
DOI: 10.1111/jth.13194 -
Allergology International : Official... Jan 2023Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and... (Review)
Review
Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.
Topics: Humans; Antibodies, Monoclonal; Plasma Kallikrein; Angioedemas, Hereditary; Treatment Outcome; Complement C1 Inhibitor Protein; Bradykinin
PubMed: 35787344
DOI: 10.1016/j.alit.2022.06.001 -
Frontiers in Immunology 2021Angioedema is a prevailing symptom in different diseases, frequently occurring in the presence of urticaria. Recurrent angioedema without urticaria (AE) can be... (Review)
Review
Angioedema is a prevailing symptom in different diseases, frequently occurring in the presence of urticaria. Recurrent angioedema without urticaria (AE) can be hereditary (HAE) and acquired (AAE), and several subtypes can be distinguished, although clinical presentation is quite similar in some of them. They present with subcutaneous and mucosal swellings, affecting extremities, face, genitals, bowels, and upper airways. AE is commonly misdiagnosed due to restricted access and availability of appropriate laboratorial tests. HAE with C1 inhibitor defect is associated with quantitative and/or functional deficiency. Although bradykinin-mediated disease results mainly from disturbance in the kallikrein-kinin system, traditionally complement evaluation has been used for diagnosis. Diagnosis is established by nephelometry, turbidimetry, or radial immunodiffusion for quantitative measurement of C1 inhibitor, and chromogenic assay or ELISA has been used for functional C1-INH analysis. Wrong handling of the samples can lead to misdiagnosis and, consequently, mistaken inappropriate approaches. Dried blood spot (DBS) tests have been used for decades in newborn screening for certain metabolic diseases, and there has been growing interest in their use for other congenital conditions. Recently, DBS is now proposed as an efficient tool to diagnose HAE with C1 inhibitor deficiency, and its use would improve the access to outbound areas and family members. Regarding HAE with normal C1 inhibitor, complement assays' results are normal and the genetic sequencing of target genes, such as exon 9 of and , is the only available method. New methods to measure cleaved high-molecular-weight kininogen and activated plasma kallikrein have emerged as potential biochemical tests to identify bradykinin-mediated angioedema. Validated biomarkers of kallikrein-kinin system activation could be helpful in differentiating mechanisms of angioedema. Our aim is to focus on the capability to differentiate histaminergic AE from bradykinin-mediated AE. In addition, we will describe the challenges developing specific tests like direct bradykinin measurements. The need for quality tests to improve the diagnosis is well represented by the variability of results in functional assays.
Topics: Angioedema; Angioedemas, Hereditary; Biomarkers; Bradykinin; Complement C1 Inhibitor Protein; DNA Mutational Analysis; Diagnosis, Differential; Diagnostic Errors; Dried Blood Spot Testing; Enzyme-Linked Immunosorbent Assay; Factor XII; Humans; Mutation; Plasminogen; Recurrence
PubMed: 34956216
DOI: 10.3389/fimmu.2021.785736 -
Frontiers in Allergy 2022Human high molecular weight kininogen (HK) is the substrate from which bradykinin is released as a result of activation of the plasma "contact" system, a cascade that... (Review)
Review
Human high molecular weight kininogen (HK) is the substrate from which bradykinin is released as a result of activation of the plasma "contact" system, a cascade that includes the intrinsic coagulation pathway, and a fibrinolytic pathway leading to the conversion of plasminogen to plasmin. Its distinction from low molecular weight kininogen (LK) was first made clear in studies of bovine plasma. While early studies did suggest two kininogens in human plasma also, their distinction became clear when plasma deficient in HK or both HK and LK were discovered. The light chain of HK is distinct and has the site of interaction with negatively charged surfaces (domain 5) plus a 6th domain that binds either prekallikrein or factor XI. HK is a cofactor for multiple enzymatic reactions that relate to the light chain binding properties. It augments the rate of conversion of prekallikrein to kallikrein and is essential for the activation of factor XI. It indirectly augments the "feedback" activation of factor XII by plasma kallikrein. Thus, HK deficiency has abnormalities of intrinsic coagulation and fibrinolysis akin to that of factor XII deficiency in addition to the inability to produce bradykinin by factor XII-dependent reactions. The contact cascade binds to vascular endothelial cells and HK is a critical binding factor with binding sites within domains 3 and 5. Prekallikrein (or factor XI) is attached to HK and is brought to the surface. The endothelial cell also secretes proteins that interact with the HK-prekallikrein complex resulting in kallikrein formation. These have been identified to be heat shock protein 90 (HSP 90) and prolylcarboxypeptidase. Cell release of urokinase plasminogen activator stimulates fibrinolysis. There are now 6 types of HAE with normal C1 inhibitors. One of them has a mutated kininogen but the mechanism for overproduction (presumed) of bradykinin has not yet been determined. A second has a mutation involving sulfation of proteoglycans which may lead to augmented bradykinin formation employing the cell surface reactions noted above.
PubMed: 35991308
DOI: 10.3389/falgy.2022.952753 -
Frontiers in Medicine 2018Plasma prekallikrein (PK) has a critical role in acute attacks of hereditary angioedema (HAE). Unlike C1 inhibitor, its levels fall during HAE attacks with resultant... (Review)
Review
Plasma prekallikrein (PK) has a critical role in acute attacks of hereditary angioedema (HAE). Unlike C1 inhibitor, its levels fall during HAE attacks with resultant cleaved high-molecular-weight kininogen. Cleavage of high-molecular-weight kininogen liberates bradykinin, the major biologic peptide that promotes the edema. How prekallikrein initially becomes activated in acute attacks of HAE is not known. PK itself is negatively associated with cardiovascular disease. High prekallikrein is associated with accelerated vascular disease in diabetes and polymorphisms of prekallikrein that reduce high-molecular-weight kininogen binding are associated with protection from cardiovascular events. Prekallikrein-deficient mice have reduced thrombosis risk and plasma kallikrein (PKa) inhibition is associated with reduced experimental gastroenterocolitis and arthritis in rodents. In sum, prekallikrein and its enzyme PKa are major targets in HAE providing much opportunity to improve the acute and chronic management of HAE. PKa inhibition also may be a target to ameliorate cardiovascular disease, thrombosis risk, and inflammation as in enterocolitis and arthritis.
PubMed: 29423395
DOI: 10.3389/fmed.2018.00003 -
Cardiology in Review 2016Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight... (Review)
Review
Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated to plasma kallikrein by activated factor XII or prolylcarboxypeptidase. Plasma kallikrein regulates the activity of multiple proteolytic cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system, and the complement pathways. As such, plasma kallikrein plays a central role in the pathogenesis of thrombosis, inflammation, and blood pressure regulation. Under physiological conditions, plasma kallikrein serves as a cardioprotective enzyme. However, its increased plasma concentration or hyperactivity perpetuates cardiovascular disease (CVD). In this article, we review the biochemistry and cell biology of plasma kallikrein and summarize data from preclinical and clinical studies that have established important functions of this serine protease in CVD states. Finally, we propose plasma kallikrein inhibitors as a novel class of drugs with potential therapeutic applications in the treatment of CVDs.
Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Molecular Targeted Therapy; Plasma Kallikrein
PubMed: 25853524
DOI: 10.1097/CRD.0000000000000069