In vivo activation and functions of the protease factor XII

2014 ◽  
Vol 112 (11) ◽  
pp. 868-875 ◽  
Author(s):  
Jenny Björkqvist ◽  
Katrin Nickel ◽  
Evi Stavrou ◽  
Thomas Renné
Keyword(s):  
Cardiovascular System ◽  
Inflammatory Diseases ◽  
Contact System ◽  
Factor Xii ◽  
Hageman Factor ◽  
Current Review ◽  
Exciting Opportunity ◽  
System Factor

SummaryCombinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. The current review concentrates on activators and functions of the FXII-driven contact system in vivo. Elucidating its physiologic activities offers the exciting opportunity to develop strategies for the safe interference with both thrombotic and inflammatory diseases.

scholarly journals Coagulation factor XII in thrombosis and inflammation

Blood ◽  
2018 ◽  
Vol 131 (17) ◽  
pp. 1903-1909 ◽  
Author(s):  
Coen Maas ◽  
Thomas Renné
Keyword(s):  
Thrombus Formation ◽  
Coagulation Factor ◽  
Contact System ◽  
Inflammatory Disorder ◽  
Factor Xii ◽  
Kinin System ◽  
Disease States ◽  
Exciting Opportunity

Abstract Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII–driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII–driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.

Detection of Activation of the Contact System of Coagulation In Vitro and In Vivo: Quantitation of Activated Hageman Factor-C1-Inhibitor and Kallikrein-C1-Inhibitor Complexes by Specific Radioimmunoassays

1987 ◽  
Vol 58 (02) ◽  
pp. 778-785 ◽  
Author(s):  
J H Nuijens ◽  
C C M Huijbregts ◽  
M Cohen ◽  
G O Navis ◽  
A de Vries ◽  
...  
Keyword(s):  
Contact System ◽  
Factor Xii ◽  
Plasma Samples ◽  
C1 Inhibitor ◽  
Hageman Factor ◽  
Plasma Factor ◽  
Factor Xiia ◽  
Kallikrein Activity

SummaryRadioimmunoassays (RIAs) for the detection of C1-inhihitor (C1-Inh) complexed to either kallikrein or activated Hageman factor (factor XIIa) are described. Kallikrein-C1-Inh or factor XIIa-C1-Inh complexes were bound to Scpharosc to which monospecific antibodies against (pre)kallikrein or factor XII, respectively, were coupled. Bound complexes were subsequently detected by an incubation with affinity purified 125I-labeled antibodies against Ci-Inh. These RIAs were used to detect activation of the contact system of coagulation in vitro and in vivo. Addition of dextran sulfate (DXS) (20 μg/ml) to fresh plasma resulted at 37° C in the rapid generation of amidolytic kallikrein activity, which was maximal after 1 to 2 min of incubation and subsequently decreased within a few minutes. The generation of kallikrein activity coincided with the appearance of both kallikrein-C1-Inh and factor XIIa-C1-Inh complexes. However, in contrast to kallikrein activity, both types of complexes remained detectable in the incubation mixtures during the incubation period. Experiments with purified kallikrein, C1-Inh and partly purified β-factor XIIa, and activation experiments in plasmas deficient in either factor XII or prekallikrein, demonstrated the specificity of both RIAs. The minimal amount of DXS that resulted in the generation of measurable amounts of both types of complexes in plasma was 2-3 μg per ml. Similar experiments with kaolin showed that with limiting amounts of activator (1-2 mg/ ml), only kallikrein-C1-Inh complexes were detected in plasma. When larger amounts of kaolin were added to plasma, factor XIIa-C1-Inh complexes were additionally detected in plasma. In plasma samples obtained from healthy donors under conditions that prevented activation of the contact system in vitro, very low levels of both factor XIIa-C1-Inh and kallikrein-C1-Inh complexes were measured, representing approximately 0.3% activation of both factor XII and prekallikrein. In serial plasma samples from a patient with adult respiratory distress syndrome, increased levels of both types of complexes were detected. The radioimmunoassays described in this paper provide useful tools to detect activation of the contact system in vitroas well as in vivo.

DEMONSTRATION OF Cl-INHIBITOR COMPLEXES IN PLASMA BY HIGHLY SENSITIVE RADIOIMMUNOASSAYS USING A MONOCLONAL ANTIBODY AGAINST A NEODETERMINANT ON COMPLEXED Cl-INHIBITOR

1987 ◽  
Author(s):  
J H Nuijens ◽  
C C M Huijbregets ◽  
L G Thijs ◽  
C E Hack
Keyword(s):  
Monoclonal Antibody ◽  
Contact System ◽  
Factor Xii ◽  
Optimal Conditions ◽  
Spleen Cells ◽  
Highly Sensitive ◽  
Factor Xiia

Levels of factor XIIa- and kallikrein-Cl inhibitor (Cl-Inh) complexes in plasma reflect activation of the contact system in vivo. Here, we report the development of radioimmunoassays (RIAs) for these complexes using a monoclonal antibody (mAb K0K12) that reacts with a neodeterminant exposed on Cl-Inh after interaction with proteases. mAb K0K12 was obtained by a fusion experiment with spleen cells of a mouse hyperimmunized with Cl-Inh complexes.Experiments with purified Cl-Inh incubated with either Cls or elastase revealed that the determinant for mAb KOK12 is exposed on complexed as well as proteolytically inactivated (modified) Cl-Inh.Radioimmunoassays (RIAs) for the detection of factor Xlla-Cl-Inh and kallikrein-Cl-Inh complexes were performed as follows: mAb K0K12 was coupled to Sepharose and incubated with the sample to be tested. Binding of Cl-Inh complexes was detected by a subsequent incubation with 125I-antibodies against factor XII or (pre)kallikrein.With these RIAs, activation of 0.1% of factor XII or prekal-likrein in plasma is easily detected.Optimal conditions for blood sampling and processing were established, i.e. conditions that prevented any in vitro activation of factor XII and prekallikrein. Levels of factor XIIa-Cl-Inh and kallikrein-Cl-Inh complexes in plasma samples from normal donors were less than 0.1 U/ml (100 U/ml is the maximal amount of Cl-Inh complexes generated in pooled plasma by DXS). Considerably higher, and fluctuating levels were observed in patients with diseases such as septicaemia. These highly sensitive RIAs will facilitate studies concerning the role of the contact system in human pathophysiology.

Participation of Hageman Factor Dependent Pathways in Human Disease States

1977 ◽  
Vol 38 (04) ◽  
pp. 0751-0775 ◽  
Author(s):  
Robert W. Colman ◽  
Patrick Y. Wong
Keyword(s):  
Human Disease ◽  
Gouty Arthritis ◽  
Factor Xii ◽  
Hageman Factor ◽  
Disease States ◽  
Artery Disease ◽  
Extracorporeal Bypass ◽  
Allergic Disorders

SummaryAbnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro changes, do not cause in vivo difficulties. In contrast, deficiency of Cl esterase inhibitor (hereditary angioedema) results in significant morbidity and mortality. Acquired diseases may exhibit decreased synthesis of these three proteins in cirrhosis and dengue fever. In vivo activation of factor XII initiated pathways occur in septic shock, disseminated or localized intravascular coagulation, typhoid fever, polycythemia vera, hyperbetalipoproteinemia, coronary artery disease, nephrotic syndrome, transfusion reactions, hemodialysis and extracorporeal bypass. Activation of both the intrinsic system and tissue mediators contribute to the vasomotor phenomena in carcinoid syndrome and postgastrectomy dumping. Roles for factor XII, prekallikrein and kininogen have been suggested in gouty arthritis, allergic disorders and cystic fibrosis but the evidence is not yet convincing in these disorders.

Basic Mechanisms of Arterial and Venous Thrombosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-1-SCI-1
Author(s):  
Thomas Renné
Keyword(s):  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Contact System ◽  
Large Animal ◽  
Inflammatory Disorder ◽  
Factor Xii ◽  
Kinin System ◽  
Large Animal Models

Abstract Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. This system starts a cascade of procoagulant and proinflammatory reactions via the intrinsic pathway of coagulation, and the bradykinin producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge. This presentation will summarize roles of the FXII-driven contact system in vivo. Genetically altered mice and large animal models have shown that FXII is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting FXII protected from cerebral ischemia without interfering with hemostasis. In contrast, excess FXII activity is associated with a life threatening inflammatory disorder, hereditary angioedema. Platelet polyphosphate (an inorganic polymer), neutrophil extracellular traps (NETs) and mast cell heparin activate FXII with implications on the initiation of thrombosis and edema. A key aspect of the talk will be the analysis of common principles, interactions and cross-talk between coagulation and inflammation, and the use of the novel FXII blocking antibody 3F7 in cardiopulmonary bypass system. Elucidating the FXII-driven contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

Cardiovascular Effects of Micromeria graeca (L.) Benth. ex Rchb in Normotensive and Hypertensive Rats

2020 ◽  
Vol 20 (8) ◽  
pp. 1253-1261
Author(s):  
Mourad Akdad ◽  
Mohamed Eddouks
Keyword(s):  
Blood Pressure ◽  
Cardiovascular System ◽  
Arterial Blood Pressure ◽  
Antihypertensive Activity ◽  
Computer Assisted ◽  
Hypertensive Rats ◽  
Vasorelaxant Effect ◽  
Arterial Blood

Aims: The present study was performed in order to analyze the antihypertensive activity of Micromeria graeca (L.) Benth. ex Rchb. Background: Micromeria graeca (L.) Benth. ex Rchb is an aromatic and medicinal plant belonging to the Lamiaceae family. This herb is used to treat various pathologies such as cardiovascular disorders. Meanwhile, its pharmacological effects on the cardiovascular system have not been studied. Objective: The present study aimed to evaluate the effect of aqueous extract of aerial parts of Micromeria graeca (AEMG) on the cardiovascular system in normotensive and hypertensive rats. Methods: In this study, the cardiovascular effect of AEMG was evaluated using in vivo and in vitro investigations. In order to assess the acute effect of AEMG on the cardiovascular system, anesthetized L-NAME-hypertensive and normotensive rats received AEMG (100 mg/kg) orally and arterial blood pressure parameters were monitored during six hours. In the sub-chronic study, rats were orally treated for one week, followed by blood pressure assessment during one week of treatment. Blood pressure was measured using a tail-cuff and a computer-assisted monitoring device. In the second experiment, isolated rat aortic ring pre-contracted with Epinephrine (EP) or KCl was used to assess the vasorelaxant effect of AEMG. Results: Oral administration of AEMG (100 mg/kg) provoked a decrease of arterial blood pressure parameters in hypertensive rats. In addition, AEMG induced a vasorelaxant effect in thoracic aortic rings pre-contracted with EP (10 μM) or KCl (80 mM). This effect was attenuated in the presence of propranolol and methylene blue. While in the presence of glibenclamide, L-NAME, nifedipine or Indomethacin, the vasorelaxant effect was not affected. Conclusion: This study showed that Micromeria graeca possesses a potent antihypertensive effect and relaxes the vascular smooth muscle through β-adrenergic and cGMP pathways.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

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