What We Know About Kininogen Structure – Importance for Function and Perspectives from Cryo-EM

10.20944/preprints202110.0342.v1 ◽

2021 ◽

Author(s):

Michal Błażej Ponczek

Keyword(s):

Spatial Structure ◽

Blood Coagulation ◽

Atomic Level ◽

Coagulation Cascade ◽

Intrinsic Pathway ◽

Extrinsic Pathway ◽

Kinin System ◽

Pathway Activation ◽

Kallikrein Kinin System ◽

Treatment Application

Kininogens are multidomain glycoproteins found in the blood of most vertebrates. They are important in the blood coagulation cascade pathways - in intrinsic pathway activation leading to thrombin generation partially independently from tissue factor dependent extrinsic pathway, connecting blood coagulation with the kallikrein-kinin system. Nothing is known about the shape on atomic level therefore the endeavor to obtain the good-quality spatial structure of kininogens is important for a better understanding of their role in disease and treatment. Application of cryo-EM is important for solving the spatial structure of kininogens, drawing new frontiers in understanding the function and opening new pathways for drug development.

Download Full-text

The dual role of the contact system in bacterial infectious disease

Thrombosis and Haemostasis ◽

10.1160/th07-01-0051 ◽

2007 ◽

Vol 98 (09) ◽

pp. 497-502 ◽

Cited By ~ 80

Author(s):

Inga-Maria Frick ◽

Lars Björck ◽

Heiko Herwald

Keyword(s):

Vascular Endothelium ◽

Blood Cells ◽

State Of The Art ◽

Contact System ◽

Intrinsic Pathway ◽

Kinin System ◽

Inflammatory Reactions ◽

Bacterial Infectious Disease ◽

Kallikrein Kinin System

SummaryHemostasis is a sensitive and tightly regulated process, involving the vascular endothelium and blood cells as well as factors of the coagulation and fibrinolytic cascades. Over the last four decades evidence has accumulated that during infection, inflammatory mediators from the microbe and/or host are capable to modulate the equilibrium between the procoagulant and anticoagulant status of the host. Dependent on the mode of activation, these changes can cause either local or systemic inflammatory reactions that may be beneficial or deleterious to the human host. The present review aims to present the state of the art with respect to the role of the contact system (also known as the intrinsic pathway of coagulation or the kallikrein/kinin system) in innate immunity and systemic inflammatory reactions.

Download Full-text

Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2014810118 ◽

2021 ◽

Vol 118 (3) ◽

pp. e2014810118

Author(s):

Katherine J. Kearney ◽

Juliet Butler ◽

Olga M. Posada ◽

Clare Wilson ◽

Samantha Heal ◽

...

Keyword(s):

Thrombin Generation ◽

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Coagulation Factor ◽

Factor Ix ◽

Coagulation Cascade ◽

Contact Activation ◽

Kinin System ◽

Fibrin Formation ◽

Kallikrein Kinin System

Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined.

Download Full-text

Stimulation of bone resorption by the kallikrein-kinin system and the coagulation cascade

Acta Orthopaedica Scandinavica ◽

10.3109/17453679509157646 ◽

1995 ◽

Vol 66 (sup266) ◽

pp. 45-50 ◽

Cited By ~ 1

Author(s):

Ulf H Lerner

Keyword(s):

Bone Resorption ◽

Coagulation Cascade ◽

Kinin System ◽

Kallikrein Kinin System ◽

Stimulation Of

Download Full-text

Intrinsic pathway of blood coagulation contributes to thrombogenicity of atherosclerotic plaque

Blood ◽

10.1182/blood-2001-11-0140 ◽

2002 ◽

Vol 99 (12) ◽

pp. 4475-4485 ◽

Cited By ~ 38

Author(s):

Natalya M. Ananyeva ◽

Diana V. Kouiavskaia ◽

Midori Shima ◽

Evgueni L. Saenko

Keyword(s):

Blood Coagulation ◽

Thrombus Formation ◽

Intrinsic Factor ◽

Density Lipoprotein ◽

Fold Increase ◽

Intrinsic Pathway ◽

Extrinsic Pathway ◽

Thrombin Formation

Thrombosis is the major mechanism underlying acute complications of atherosclerosis. Although thrombogenicity of atherosclerotic plaques has been ascribed to activation of the extrinsic pathway of blood coagulation, in the present study we investigated contribution of the intrinsic factor VIII (fVIII)–dependent pathway. We found that in vitro exposure of human macrophages and smooth muscle cells (SMCs) to atherogenic oxidized low-density lipoprotein (oxLDL) enhances their ability to support activity of 2 major complexes of the intrinsic pathway, Xase and prothrombinase, leading to a 20- and 10-fold increase in thrombin formation, respectively. In contrast, human aortic endothelial cells were less responsive to oxLDL. The increase in the intrinsic procoagulant activity was related to formation of additional fVIII binding sites due to enhanced translocation of phosphatidylserine to the outer surface of oxLDL-treated cells and a 5-fold higher affinity of interaction between components of the Xase complex, activated factors VIII and IX. Processes occurring at early apoptotic stages, including changes in the cell membrane induced by free radicals, may be related to activation of the intrinsic pathway as suggested by effects of inhibitors of early apoptosis on thrombin formation. Immunohistochemical studies on human atherectomy specimens revealed the presence of fVIII in the vicinity of macrophages and SMCs in atheromatous regions with massive deposits of oxLDL, supporting the possible involvement of the intrinsic pathway in thrombus formation in vivo. Our data predict that the intrinsic pathway significantly enhances thrombogenicity of atherosclerotic lesions after removal of the endothelial layer and exposure of SMCs and macrophages to blood flow.

Download Full-text

Regulation of bone metabolism by the kallikrein-kinin system, the coagulation cascade, and the acute-phase reactants

Oral Surgery Oral Medicine Oral Pathology ◽

10.1016/0030-4220(94)90043-4 ◽

1994 ◽

Vol 78 (4) ◽

pp. 481-493 ◽

Cited By ~ 42

Author(s):

Ulf H. Lerner

Keyword(s):

Bone Metabolism ◽

Acute Phase ◽

Coagulation Cascade ◽

Kinin System ◽

Acute Phase Reactants ◽

Kallikrein Kinin System

Download Full-text

The Kallikrein-Kinin System: A Functional Role of Plasma Kallikrein and Kininogen in Blood Coagulation

Biological Functions of Proteinases ◽

10.1007/978-3-642-81395-5_23 ◽

1979 ◽

pp. 243-259 ◽

Cited By ~ 9

Author(s):

S. Iwanaga ◽

H. Kato ◽

T. Sugo ◽

N. Ikari ◽

N. Hashimoto ◽

...

Keyword(s):

Blood Coagulation ◽

Functional Role ◽

Plasma Kallikrein ◽

Kinin System ◽

System A ◽

Kallikrein Kinin System

Download Full-text

Tantalum-containing mesoporous bioactive glass powder for hemostasis

Journal of Biomaterials Applications ◽

10.1177/0885328220965150 ◽

2020 ◽

pp. 088532822096515

Author(s):

Malvika Nagrath ◽

Reid Gallant ◽

Alireza Rahimnejad Yazdi ◽

Andrew Mendonca ◽

Saidur Rahman ◽

...

Keyword(s):

Zeta Potential ◽

Blood Coagulation ◽

Intrinsic Pathway ◽

Extrinsic Pathway ◽

Bioactive Glasses ◽

In Vitro Methods ◽

Hemostatic Agents ◽

Negative Zeta Potential ◽

Mesoporous Bioactive Glass

This study evaluates the hemostatic properties of tantalum-containing mesoporous bioactive glasses (Ta-MBGs) through a suite of in-vitro methods: hemolysis percentage, zeta potential, blood coagulation assays (Activated Partial Thromboplastin Time – APTT and Prothrombin Time - PT) and cytotoxicity tests. Five compositions of Ta-MBG, with x mol% Ta2O5 added to the glass series (80- x)SiO2-15CaO-5P2O5- xTa2O5 where x=0 (0Ta), x=0.5 (0.5Ta), x=1 (1Ta), x=5 (5Ta), and x=10 (10Ta) mol%, were synthesised. The hemostatic potential of all the Ta-MBGs was confirmed by their negative zeta potential (–23 to –31 mV), which enhances the intrinsic pathway of blood coagulation. The hemolysis percentages of all Ta-MBGs except 10Ta showed statistically significant reductions compared to the same experiments carried out both in the absence of a sample (‘no treatment’ group) and in the presence of 10Ta. These observations validate the consideration of Ta-MBGs as hemostatic agents as they do not cause significant lysis of red blood cells. Cytotoxicity analysis revealed that Ta-MBGs had no effect on bovine fibroblast viability. Furthermore, a reduction in both APTT (a test to evaluate the intrinsic pathway of coagulation) and PT (a test to evaluate the extrinsic pathway) signified enhancement of hemostasis: 5Ta caused a significant reduction in APTT compared to ‘no treatment’, 1Ta and 10Ta and a significant reduction in PT compared to 0Ta. Therefore, we conclude that 5mol% of Ta optimised the hemostatic properties of these mesoporous bioactive glasses.

Download Full-text