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Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
There is a complex relationship among the activation of Factor XII, activation of Factor XI, formation of plasmin, formation of kallikrein, and the effect of high-molecular weight kininogen (Figure 23). Subjects with prekallikrein deficiency elicit no special symptoms, but their blood exerts a prolonged clotting time in vitro. They show a defective surface-mediated activation of fibrinolysis and defective permeability enhancement.397,499 In this disease condition kallikrein accelerates the activation of Factor XII and Factor VII, and enhances the conversion of kininogen to bradykinin.245 A defect in kininogen production is due to the deficiency of high-molecular weight kininogen, and it prolongs clotting time in vitro, with an impaired generation of the vascular permeability factor. Various steps involved in blood coagulation and vascular alterations are presented in a scheme (Figure 24).
The Fibrinolytic Response to Intravenous Endotoxin Administration
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Plasminogen can be activated by the contact system through the generation of the proteolytic enzyme kallikrein. Components of the contact system were studied using quantitative antigenic and functional assays.41 Following endotoxin administration, functional prekallikrein levels fell at 2 h and remained low at 5 and 24 h postendotoxin. Prekallikrein antigen levels were depressed at 5 h only. Factor XI was decreased by 2 h, remained depressed at 5 h, and returned to normal values at 24 h after the infusion of endotoxin. No changes occurred in the functional levels of high-molecular-weight kininogen or anu-thrombin III. Activation of the contact system was further manifested by a rise in the concentration of the complex that forms between kallikrein and one of its inhibitors, α2-macroglobulin. The Ok-macroglobulin-kallikrein complexes were elevated fourfold by 3 h, fivefold at 5 h, and returned to normal by 24 h. Thus, another plasminogen activator, kallikrein, was generated in parallel with the earlier release of t-PA at 1 h. This contact activation may enhance or amplify the fibrinolytic response during the initial phases of endotoxemia.41
Coagulation Theory, Principles, and Concepts
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
As mention earlier, prekallikrein is a component of the contact activation system of blood clotting. Kallikrein will rapidly convert single-chained tPA to two-chained tPA, and is thought to be involved in the conversion of prourokinase to urokinase. In the test tube, factor XII activation is accompanied by the formation of plasmin. This activation of fibrinolysis depends on the presence of both urokinase and kallikrein. There has been some speculation as to whether this mechanism of plasmin formation has any significance in in-vivo fibrinolysis.
Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency
Published in Expert Opinion on Emerging Drugs, 2022
Andrea Zanichelli, Vincenzo Montinaro, Massimo Triggiani, Francesco Arcoleo, Debora Visigalli, Mauro Cancian
In conclusion, understanding the pathogenetic mechanism of hereditary angioedema allowed multiple number of drugs to be available and under development, a fact otherwise unexplainable considering the rarity of the disease. However, several drawbacks in existing treatments prompted pharmaceutical companies to study new drugs, possibly characterized by more convenient administration routes, less side effects, and a lower number of administrations. Regarding the mechanism of action of investigational drugs, KVD-824, KVD-900, and ATN-249 target kallikrein. PHA-121 seems more potent than icatibant in inhibiting the bradykinin 2 receptor. Garadacimab blocks a hitherto untargeted molecule, i.e. factor XIIa. Donidalorsen inhibits prekallikrein. Finally, gene therapy might cure a chronic, life-threatening disease. Preliminary data about effectiveness, safety, and conveniency of new products are promising. After marketing, costs considerations will need to be made.
Subclinical macroangiopathic target organ damage in type 1 diabetes mellitus patients
Published in Blood Pressure, 2020
Magdalena Błaszkowska, Anna Shalimova, Bogumił Wolnik, Elżbieta Orłowska-Kunikowska, Beata Graff, Michał Hoffmann, Peter Nilsson, Jacek Wolf, Krzysztof Narkiewicz
Based on DCCT/EDIC data, other indicators of vascular complications in T1DM include plasma prekallikrein, which levels were significantly positively associated with BMI, HA1c, systolic blood pressure, total cholesterol, LDL cholesterol, and triglycerides (but not with age, sex, T1DM duration or HDL cholesterol). Plasma prekallikrein was also significantly positively associated with progression of both internal and combined IMT, suggesting that it can be regarded as a risk factor of subclinical vascular disease in T1DM [78].
A review of emerging factor XI inhibitors
Published in Expert Opinion on Emerging Drugs, 2023
Sandra Elsheikh, Nicola Tidbury, Gregory Y.H. Lip
When the contact pathway is activated, factor XII is converted to activated factor XII (factor XIIa). Factor XIIa causes cleavage of prekallikrein to active kallikrein (which activates factor XII as well) and initiates the activation of factor XI. Activated factor XI (factor XIa) then activates factor IX which in turn activates factor X leading to the common pathway of thrombin activation and fibrin formation [17].