Plasma Kallikrein Cleaved H-kininogen: An End-Point Marker for Contact Activation in vitro and ex vivo

Objectives The contact system consists of coagulation factor XII (FXII), prekallikrein, and H-kininogen (HK) and plays important roles in many diseases. Plasma kallikrein (PKa) cleaved HK (cHK) is a marker of contact activation. Presently, we developed a specific and precise enzyme-linked immunosorbent assay (ELISA) for determination of cHK in vitro and ex vivo. Methods Cleaved HK specific mouse monoclonal antibodies (mAbs) were generated using a peptide corresponding to the PKa cleavage site on HK as immunogen. ELISA, surface plasmon resonance analysis, and immunoprecipitation established the specificity of the antibody, which subsequently was used in a sandwich ELISA. The analytical imprecision and the concentration of cHK in a reference population and in women receiving oral contraceptives (OC) were determined. cHK was assessed in vitro in plasma exposed to polytetrafluoroethylene, silicone, and glass tubes. Results The selected mAb showed excellent specificity towards cHK. The intra-assay and inter-assay CV of the ELISA were 3.6 and 6.0%, respectively. The reference population (60 women, 60 men) displayed a median cHK plasma concentration of 1.38 μg/mL and a reference interval of 0.82 – 2.56 μg/mL. Women receiving OC had significantly higher concentrations, p < 0.001. cHK was significantly elevated in plasma exposed to polytetrafluoroethylene, p = 0.001, and glass, p < 0.0001. Conclusion The ELISA showed excellent precision and specificity. cHK assessment ex vivo demonstrated ongoing contact activation in healthy individuals, augmented by OC. The cHK antibody and the ELISA could be promising tools in contact activation related diseases and in vitro investigations of the plasma compatibility of blood contacting biomaterials.

[1]  Byeong-Chae Kim,et al.  Plasma contact factors as novel biomarkers for diagnosing Alzheimer’s disease , 2021, Biomarker research.

[2]  J. Gram,et al.  Effect of Anabolic–Androgenic Steroid Abuse on the Contact Activation System , 2021, Thrombosis and Haemostasis.

[3]  C. Maas.  Plasminflammation—An Emerging Pathway to Bradykinin Production , 2019, Front. Immunol..

[4]  M. Maitz,et al.  The blood compatibility challenge Part 3: Material associated activation of blood cascades and cells. , 2019, Acta biomaterialia.

[5]  S. Strickland,et al.  A novel detection method of cleaved plasma high-molecular-weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment , 2018, Alzheimer's & dementia.

[6]  T. Renné,et al.  Coagulation factor XII in thrombosis and inflammation. , 2018, Blood.

[7]  T. Renné,et al.  Cleaved kininogen as a biomarker for bradykinin release in hereditary angioedema. , 2017, The Journal of allergy and clinical immunology.

[8]  C. Maas,et al.  The Search for Biomarkers in Hereditary Angioedema , 2017, Front. Med..

[9]  K. Skjoedt,et al.  Fast form alpha-2-macroglobulin - A marker for protease activation in plasma exposed to artificial surfaces. , 2017, Clinical biochemistry.

[10]  T. Renné,et al.  Factor XII Contact Activation , 2017, Seminars in Thrombosis and Hemostasis.

[11]  M. Cicardi,et al.  High‐molecular‐weight kininogen cleavage correlates with disease states in the bradykinin‐mediated angioedema due to hereditary C1‐inhibitor deficiency , 2014, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[12]  J. Floege,et al.  Factor XII activation markers do not reflect FXII dependence of thrombin generation induced by polyvinylchloride , 2013, Journal of Materials Science: Materials in Medicine.

[13]  G. Lalmanach,et al.  Kininogens: More than cysteine protease inhibitors and kinin precursors. , 2010, Biochimie.

[14]  H. ten Cate,et al.  Inhibitor complexes of the plasma kallikrein–kinin system and outcome prediction in patients following admission for chest pain , 2009, Journal of thrombosis and haemostasis : JTH.

[15]  Buddy D Ratner,et al.  The catastrophe revisited: blood compatibility in the 21st Century. , 2007, Biomaterials.

[16]  R. Colman,et al.  Fifty years of research on the plasma kallikrein-kinin system: From protein structure and function to cell biology and in-vivo pathophysiology , 2007, Thrombosis and Haemostasis.

[17]  L. Juliano,et al.  Differences in substrate and inhibitor sequence specificity of human, mouse and rat tissue kallikreins. , 2004, The Biochemical journal.

[18]  J. Rouleau,et al.  Bradykinin and des-Arg(9)-bradykinin metabolic pathways and kinetics of activation of human plasma. , 2001, American journal of physiology. Heart and circulatory physiology.

[19]  D. Shaw,et al.  Two‐chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5 , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  J. Morrow,et al.  Metabolism of bradykinin In vivo in humans: identification of BK1-5 as a stable plasma peptide metabolite. , 2000, The Journal of pharmacology and experimental therapeutics.

[21]  A. Schmaier,et al.  Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. , 1997, Blood.

[22]  R. Colman,et al.  The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy. , 1994, The Journal of biological chemistry.

[23]  A. Schmaier,et al.  Domain 3 of kininogens contains a cell-binding site and a site that modifies thrombin activation of platelets. , 1992, The Journal of biological chemistry.

[24]  A. Schmaier,et al.  Low molecular weight kininogen binds to platelets to modulate thrombin-induced platelet activation. , 1991, The Journal of biological chemistry.

[25]  S. Higashiyama,et al.  Heavy chain of human high molecular weight and low molecular weight kininogens binds calcium ion. , 1987, Biochemistry.

[26]  A. Barrett,et al.  Human low-Mr kininogen contains three copies of a cystatin sequence that are divergent in structure and in inhibitory activity for cysteine proteinases. , 1986, The Biochemical journal.

[27]  O. Ratnoff,et al.  Rapid fibrinolysis, augmented Hageman factor (factor XII) titers, and decreased C1 esterase inhibitor titers in women taking oral contraceptives. , 1980, The Journal of laboratory and clinical medicine.

[28]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.

[29]  J. Margolis,et al.  Activation of plasma by contact with glass: evidence for a common reaction which releases plasma kinin and initiates coagulation , 1958, The Journal of physiology.

[30]  Anna E. Engberg,et al.  Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood. , 2016, Biomaterials.