The Experts below are selected from a list of 1503 Experts worldwide ranked by ideXlab platform
Thomas Renné - One of the best experts on this subject based on the ideXlab platform.
-
Coagulation Factor XII in thrombosis and inflammation.
Blood, 2018Co-Authors: Coen Maas, Thomas RennéAbstract: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.
-
Factor XII as a therapeutic target in thromboembolic and inflammatory diseases
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Katrin F Nickel, Andy T Long, Tobias A Fuchs, Lynn M Butler, Thomas RennéAbstract:Coagulation Factor XII (FXII, Hageman Factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII’s unique...
-
the alzheimer s disease peptide β amyloid promotes thrombin generation through activation of Coagulation Factor XII
Journal of Thrombosis and Haemostasis, 2016Co-Authors: Daria Zamolodchikov, Thomas Renné, Sidney StricklandAbstract:Essentials How the Alzheimer's disease (AD) peptide β-amyloid (Aβ) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. Aβ triggers FXII-dependent FXI and thrombin activation, evidence of which is seen in AD plasma. Aβ-triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target. SummaryBackground β-Amyloid (Aβ) is a key pathologic element in Alzheimer's disease (AD), but the mechanisms by which it disrupts neuronal function in vivo are not completely understood. AD is characterized by a prothrombotic state, which could contribute to neuronal dysfunction by affecting cerebral blood flow and inducing inflammation. The plasma protein Factor XII triggers clot formation via the intrinsic Coagulation cascade, and has been implicated in thrombosis. Objectives To investigate the potential for Aβ to contribute to a prothrombotic state. Methods and results We show that Aβ activates FXII, resulting in FXI activation and thrombin generation in human plasma, thereby establishing Aβ as a possible driver of prothrombotic states. We provide evidence for this process in AD by demonstrating decreased levels of FXI and its inhibitor C1 esterase inhibitor in AD patient plasma, suggesting chronic activation, inhibition and clearance of FXI in AD. Activation of the intrinsic Coagulation pathway in AD is further supported by elevated fibrin levels in AD patient plasma. Conclusions The ability of Aβ to promote Coagulation via the FXII-driven contact system identifies new mechanisms by which it could contribute to neuronal dysfunction and suggests potential new therapeutic targets in AD.
-
enhanced cortical reperfusion protects Coagulation Factor XII deficient mice from ischemic stroke as revealed by high field mri
NeuroImage, 2010Co-Authors: Thomas Renné, Christoph Kleinschnitz, Mirko Pham, Xavier Helluy, Andreas J Bartsch, Madeleine Austinat, Volker C Behr, Bernhard NieswandtAbstract:Abstract Intrinsic Coagulation Factor XII deficient ( FXII −/− ) mice are protected from ischemic stroke. To elucidate underlying mechanisms we investigated the early ischemic period in vivo by multimodal magnetic resonance imaging (MRI) at 17.6 Tesla. Cerebral ischemia was induced by either t ransient (60 min) or p ermanent occlusion of the middle cerebral artery ( t / p MCAO). 10 FXII − / − mice underwent t- , 10 FXII − / − mice p - and 10 Wildtype (Wt) mice t MCAO. Cerebral blood flow (CBF), diffusion-weighted-imaging (DWI) and T2-relaxometry were measured at 2 h and 24 h after MCAO. Outcome measures were evaluated after motion correction and normalization to atlas space. 2 h after t MCAO CBF reduction was similar in FXII − / − and Wt mice extending over cortical (CBF (ml/100 g/min) 33.6 ± 6.9 vs. 35.3 ± 4.6, p = 0.42) and subcortical regions (25.7 ± 4.5 vs. 31.6 ± 4.0, p = 0.17). At 24 h, recovery of cortical CBF by +36% was observed only in t MCAO FXII − / − mice contrasting a further decrease of – 30% in Wt mice after t MCAO ( p = 0.02, F (1,18) = 6.24). In FXII − / − mice in which patency of the MCA was not restored ( p MCAO) a further decrease of − 75% was observed. Cortical reperfusion in t MCAO FXII − / − mice was related to a lower risk of infarction of 59% vs. 93% in Wt mice ( p = 0.04). Subcortical CBF was similarly decreased in both t MCAO groups (Wt and FXII − / − ) relating to a similar risk of infarction of 89% (Wt) vs. 99% ( FXII − / − , p = 0.17). Deficiency of FXII allows neocortical reperfusion after t MCAO and rescues brain tissue by this mechanism. This study supports the concept of FXII as a promising new target for stroke prevention and therapy.
-
Increased activity of Coagulation Factor XII (Hageman Factor) causes hereditary angioedema type III.
American Journal of Human Genetics, 2006Co-Authors: Sven Cichon, Thomas Renné, Ludovic Martin, Hans Christian Hennies, Felicitas Müller, Karen Van Driessche, Anna Karpushova, Wim Stevens, Roberto Colombo, Christian DrouetAbstract:Hereditary angioedema (HAE) is characterized clinically by recurrent acute skin swelling, abdominal pain, and potentially life-threatening laryngeal edema. Three forms of HAE have been described. The classic forms, HAE types I and II, occur as a consequence of mutations in the C1-inhibitor gene. In contrast to HAE types I and II, HAE type III has been observed exclusively in women, where it appears to be correlated with conditions of high estrogen levels--for example, pregnancy or the use of oral contraceptives. A recent report proposed two missense mutations (c.1032C-->A and c.1032C-->G) in F12, the gene encoding human Coagulation Factor XII (FXII, or Hageman Factor) as a possible cause of HAE type III. Here, we report the occurrence of the c.1032C-->A (p.Thr328Lys) mutation in an HAE type III-affected family of French origin. Investigation of the F12 gene in a large German family did not reveal a coding mutation. Haplotype analysis with use of microsatellite markers is compatible with locus heterogeneity in HAE type III. To shed more light on the pathogenic relevance of the HAE type III-associated p.Thr328Lys mutation, we compared FXII activity and plasma levels in patients carrying the mutation with that of healthy control individuals. Our data strongly suggest that p.Thr328Lys is a gain-of-function mutation that markedly increases FXII amidolytic activity but that does not alter FXII plasma levels. We conclude that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema. Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected with HAE type III. The results of our study represent an important step toward an understanding of the molecular processes involved in HAE type III and provide diagnostic and possibly new therapeutic opportunities.
Bernhard Nieswandt - One of the best experts on this subject based on the ideXlab platform.
-
targeting Coagulation Factor XII as a novel therapeutic option in brain trauma
Annals of Neurology, 2016Co-Authors: Christiane Albertweissenberger, Bernhard Nieswandt, Peter Schmidt, Cameliamaria Monoranu, Irina Alafuzoff, Sarah C Hopp, Stine Mencl, Michael Bieber, Michael K Schuhmann, Christian StetterAbstract:OBJECTIVE: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting Factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.METHODS: We investigated the impact of genetic deficiency of Factor XII and acute inhibition of activated Factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.RESULTS: Our study showed that both genetic deficiency of Factor XII and an inhibition of activated Factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human Factor XII in Factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.INTERPRETATION: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. Ann Neurol 2016;79:970-982. (Less)
-
blood Coagulation Factor XII a neglected player in stroke pathophysiology
Journal of Molecular Medicine, 2012Co-Authors: Mirko Pham, Bernhard Nieswandt, Guido Stoll, Martin Bendszus, Christoph KleinschnitzAbstract:Ischemic stroke is a devastating disease which, in most cases, is caused by thrombotic occlusion of brain arteries. The molecular mechanisms involved in microvascular thrombus formation during focal cerebral ischemia are not well understood. As a consequence, the current antithrombotic drugs used to treat acute stroke or prevent stroke recurrence either show limited efficacy or put patients at risk for serious bleeding complications. The serine protease blood Coagulation Factor XII (FXII) initiates the intrinsic pathway of Coagulation which, together with the extrinsic pathway, culminates in the formation of fibrin. A physiological function of FXII in clot formation and hemostasis in vivo has been questioned for more than 50 years. This was mainly due to the fact that hereditary FXII deficiency does not induce any bleeding phenotype in humans. However, recent studies in transgenic mice challenged this concept by demonstrating that FXII deficiency prevents pathological thrombus formation, but does not affect regular hemostasis. These findings entailed investigations in relevant disease models of thromboembolism including ischemic stroke. The present review summarizes the pathophysiological role of FXII in experimental cerebral ischemia and highlights novel therapeutic strategies based on FXII inhibition.
-
enhanced cortical reperfusion protects Coagulation Factor XII deficient mice from ischemic stroke as revealed by high field mri
NeuroImage, 2010Co-Authors: Thomas Renné, Christoph Kleinschnitz, Mirko Pham, Xavier Helluy, Andreas J Bartsch, Madeleine Austinat, Volker C Behr, Bernhard NieswandtAbstract:Abstract Intrinsic Coagulation Factor XII deficient ( FXII −/− ) mice are protected from ischemic stroke. To elucidate underlying mechanisms we investigated the early ischemic period in vivo by multimodal magnetic resonance imaging (MRI) at 17.6 Tesla. Cerebral ischemia was induced by either t ransient (60 min) or p ermanent occlusion of the middle cerebral artery ( t / p MCAO). 10 FXII − / − mice underwent t- , 10 FXII − / − mice p - and 10 Wildtype (Wt) mice t MCAO. Cerebral blood flow (CBF), diffusion-weighted-imaging (DWI) and T2-relaxometry were measured at 2 h and 24 h after MCAO. Outcome measures were evaluated after motion correction and normalization to atlas space. 2 h after t MCAO CBF reduction was similar in FXII − / − and Wt mice extending over cortical (CBF (ml/100 g/min) 33.6 ± 6.9 vs. 35.3 ± 4.6, p = 0.42) and subcortical regions (25.7 ± 4.5 vs. 31.6 ± 4.0, p = 0.17). At 24 h, recovery of cortical CBF by +36% was observed only in t MCAO FXII − / − mice contrasting a further decrease of – 30% in Wt mice after t MCAO ( p = 0.02, F (1,18) = 6.24). In FXII − / − mice in which patency of the MCA was not restored ( p MCAO) a further decrease of − 75% was observed. Cortical reperfusion in t MCAO FXII − / − mice was related to a lower risk of infarction of 59% vs. 93% in Wt mice ( p = 0.04). Subcortical CBF was similarly decreased in both t MCAO groups (Wt and FXII − / − ) relating to a similar risk of infarction of 89% (Wt) vs. 99% ( FXII − / − , p = 0.17). Deficiency of FXII allows neocortical reperfusion after t MCAO and rescues brain tissue by this mechanism. This study supports the concept of FXII as a promising new target for stroke prevention and therapy.
-
targeting Coagulation Factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis
Journal of Experimental Medicine, 2006Co-Authors: Christoph Kleinschnitz, David Gailani, Bernhard Nieswandt, Guido Stoll, Martin Bendszus, Kai Schuh, H U Pauer, Peter Burfeind, Christoph Renne, Thomas RennéAbstract:Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of Factor XII (FXII), the protease that triggers the intrinsic pathway of Coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate Factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.
-
platelets promote Coagulation Factor XII mediated proteolytic cascade systems in plasma
Biological Chemistry, 2006Co-Authors: Julia Johne, Bernhard Nieswandt, Kai Schuh, Miroslava Pozgajova, Constanze Blume, Peter M Benz, Melanie Ullrich, Ulrich Walter, Thomas RennéAbstract:Blood Coagulation Factor XII (FXII, Hageman Factor) is a plasma serine protease which is autoactivated following contact with negatively charged surfaces in a reaction involving plasma kallikrein and high-molecular-weight kininogen (contact phase activation). Active FXII has the ability to initiate blood clotting via the intrinsic pathway of Coagulation and inflammatory reactions via the kallikrein-kinin system. Here we have determined FXII-mediated bradykinin formation and clotting in plasma. Western blotting analysis with specific antibodies against various parts of the contact Factors revealed that limited activation of FXII is sufficient to promote plasma kallikrein activation, resulting in the conversion of high-molecular-weight kininogen and bradykinin generation. The presence of platelets significantly promoted FXII-initiated bradykinin formation. Similarly, in vitro clotting assays revealed that platelets critically promoted FXII-driven thrombin and fibrin formation. In summary, our data suggest that FXII-initiated protease cascades may proceed on platelet surfaces, with implications for inflammation and clotting.
Christoph Kleinschnitz - One of the best experts on this subject based on the ideXlab platform.
-
amelioration of cognitive and behavioral deficits after traumatic brain injury in Coagulation Factor XII deficient mice
International Journal of Molecular Sciences, 2021Co-Authors: Christian Stetter, Michael Bieber, Christoph Kleinschnitz, Simon Lopezcaperuchipi, Sarah Hoppkramer, Annaleena Siren, Christiane AlbertweisenbergerAbstract:Based on recent findings that show that depletion of Factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII-/- mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII-/- mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII-/- mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII-/- mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII-/- mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.
-
blood Coagulation Factor XII a neglected player in stroke pathophysiology
Journal of Molecular Medicine, 2012Co-Authors: Mirko Pham, Bernhard Nieswandt, Guido Stoll, Martin Bendszus, Christoph KleinschnitzAbstract:Ischemic stroke is a devastating disease which, in most cases, is caused by thrombotic occlusion of brain arteries. The molecular mechanisms involved in microvascular thrombus formation during focal cerebral ischemia are not well understood. As a consequence, the current antithrombotic drugs used to treat acute stroke or prevent stroke recurrence either show limited efficacy or put patients at risk for serious bleeding complications. The serine protease blood Coagulation Factor XII (FXII) initiates the intrinsic pathway of Coagulation which, together with the extrinsic pathway, culminates in the formation of fibrin. A physiological function of FXII in clot formation and hemostasis in vivo has been questioned for more than 50 years. This was mainly due to the fact that hereditary FXII deficiency does not induce any bleeding phenotype in humans. However, recent studies in transgenic mice challenged this concept by demonstrating that FXII deficiency prevents pathological thrombus formation, but does not affect regular hemostasis. These findings entailed investigations in relevant disease models of thromboembolism including ischemic stroke. The present review summarizes the pathophysiological role of FXII in experimental cerebral ischemia and highlights novel therapeutic strategies based on FXII inhibition.
-
cou254 a specific 3 carboxamide coumarin inhibitor of Coagulation Factor XII does not protect mice from acute ischemic stroke
Experimental & Translational Stroke Medicine, 2010Co-Authors: Peter Kraft, Guido Stoll, Tobias Schwarz, Lionel Pochet, Christoph KleinschnitzAbstract:Background AntiCoagulation is an important means to prevent from acute ischemic stroke but is associated with a significant risk of severe hemorrhages. Previous studies have shown that blood Coagulation Factor XII (FXII)-deficient mice are protected from pathological thrombus formation during cerebral ischemia without bearing an increased bleeding tendency. Hence, pharmacological blockade of FXII might be a promising and safe approach to prevent acute ischemic stroke and possibly other thromboembolic disorders but pharmacological inhibitors selective over FXII are still lacking. In the present study we investigated the efficacy of COU254, a novel nonpeptidic 3-carboxamide-coumarin that selectively blocks FXII activity, on stroke development and post stroke functional outcome in mice.
-
enhanced cortical reperfusion protects Coagulation Factor XII deficient mice from ischemic stroke as revealed by high field mri
NeuroImage, 2010Co-Authors: Thomas Renné, Christoph Kleinschnitz, Mirko Pham, Xavier Helluy, Andreas J Bartsch, Madeleine Austinat, Volker C Behr, Bernhard NieswandtAbstract:Abstract Intrinsic Coagulation Factor XII deficient ( FXII −/− ) mice are protected from ischemic stroke. To elucidate underlying mechanisms we investigated the early ischemic period in vivo by multimodal magnetic resonance imaging (MRI) at 17.6 Tesla. Cerebral ischemia was induced by either t ransient (60 min) or p ermanent occlusion of the middle cerebral artery ( t / p MCAO). 10 FXII − / − mice underwent t- , 10 FXII − / − mice p - and 10 Wildtype (Wt) mice t MCAO. Cerebral blood flow (CBF), diffusion-weighted-imaging (DWI) and T2-relaxometry were measured at 2 h and 24 h after MCAO. Outcome measures were evaluated after motion correction and normalization to atlas space. 2 h after t MCAO CBF reduction was similar in FXII − / − and Wt mice extending over cortical (CBF (ml/100 g/min) 33.6 ± 6.9 vs. 35.3 ± 4.6, p = 0.42) and subcortical regions (25.7 ± 4.5 vs. 31.6 ± 4.0, p = 0.17). At 24 h, recovery of cortical CBF by +36% was observed only in t MCAO FXII − / − mice contrasting a further decrease of – 30% in Wt mice after t MCAO ( p = 0.02, F (1,18) = 6.24). In FXII − / − mice in which patency of the MCA was not restored ( p MCAO) a further decrease of − 75% was observed. Cortical reperfusion in t MCAO FXII − / − mice was related to a lower risk of infarction of 59% vs. 93% in Wt mice ( p = 0.04). Subcortical CBF was similarly decreased in both t MCAO groups (Wt and FXII − / − ) relating to a similar risk of infarction of 89% (Wt) vs. 99% ( FXII − / − , p = 0.17). Deficiency of FXII allows neocortical reperfusion after t MCAO and rescues brain tissue by this mechanism. This study supports the concept of FXII as a promising new target for stroke prevention and therapy.
-
targeting Coagulation Factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis
Journal of Experimental Medicine, 2006Co-Authors: Christoph Kleinschnitz, David Gailani, Bernhard Nieswandt, Guido Stoll, Martin Bendszus, Kai Schuh, H U Pauer, Peter Burfeind, Christoph Renne, Thomas RennéAbstract:Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of Factor XII (FXII), the protease that triggers the intrinsic pathway of Coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate Factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.
Malgorzata Wygrecka - One of the best experts on this subject based on the ideXlab platform.
-
Coagulation Factor XII regulates inflammatory responses in human lungs
European Respiratory Journal, 2017Co-Authors: Malgorzata Wygrecka, Coen Maas, Steven De Maat, Rosanna Hess, Lukasz Wujak, Christina Hesse, Katherina Sewald, Francesco Bonella, Klaus T Preissner, Philipp MarkartAbstract:Rationale: Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of Coagulation is activated and may regulate inflammatory responses in ARDS lungs. Methods: Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Measurements and Main Results: Activation of the contact system, associated with high levels of Coagulation Factor XII (Hageman Factor, FXII), plasma kallikrein and bradykinin, in ARDS lungs occurred rapidly after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS non-survivors than survivors and were positively correlated with tumor necrosis Factor (TNF)-α concentration. FXII induced the production and release of interleukin (IL)-8, IL-1β, IL-6, leukemia inhibitory Factor (LIF), CXCL5 and TNF-α in human PCLS in a kallikrein-kinin-independent manner. Conclusions: Accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis.
-
transforming growth Factor β1 induces expression of human Coagulation Factor XII via smad3 and jnk signaling pathways in human lung fibroblasts
Journal of Biological Chemistry, 2010Co-Authors: Ewa Jablonska, Philipp Markart, Klaus T Preissner, Dariusz Zakrzewicz, Malgorzata WygreckaAbstract:Coagulation Factor XII (FXII) is a liver-derived serine protease involved in fibrinolysis, Coagulation, and inflammation. The regulation of FXII expression is largely unknown. Transforming growth Factor-beta1 (TGF-beta1) is a multifunctional cytokine that has been linked to several pathological processes, including tissue fibrosis by modulating procoagulant and fibrinolytic activities. This study investigated whether TGF-beta1 may regulate FXII expression in human lung fibroblasts. Treatment of human lung fibroblasts with TGF-beta1 resulted in a time-dependent increase in FXII production, activation of p44/42, p38, JNK, and Akt, and phosphorylation and translocation into the nucleus of Smad3. However, TGF-beta1-induced FXII expression was repressed only by the JNK inhibitor and JNK and Smad3 antisense oligonucleotides but not by MEK, p38, or phosphoinositide 3-kinase blockers. JNK inhibition had no effect on TGF-beta1-induced Smad3 phosphorylation, association with Smad4, and its translocation into the nucleus but strongly suppressed Smad3-DNA complex formation. FXII promoter analysis revealed that the -299/+1 region was sufficient for TGF-beta1 to induce FXII expression. Sequence analysis of this region detected a potential Smad-binding element at position -272/-269 (SBE-(-272/-269)). Chromatin immunoprecipitation and streptavidin pulldown assays demonstrated TGF-beta1-dependent Smad3 binding to SBE-(-272/-269). Mutation or deletion of SBE-(-272/-269) substantially reduced TGF-beta1-mediated activation of the FXII promoter. Clinical relevance was demonstrated by elevated FXII levels and its co-localization with fibroblasts in the lungs of patients with acute respiratory distress syndrome. Our results show that JNK/Smad3 pathway plays a critical role in TGF-beta1-induced FXII expression in human lung fibroblasts and implicate its possible involvement in pathological conditions characterized by elevated TGF-beta1 levels.
-
transforming growth Factor β1 induces expression of human Coagulation Factor XII via smad3 and jnk signaling pathways in human lung fibroblasts
Journal of Biological Chemistry, 2010Co-Authors: Ewa Jablonska, Philipp Markart, Klaus T Preissner, Dariusz Zakrzewicz, Malgorzata WygreckaAbstract:Coagulation Factor XII (FXII) is a liver-derived serine protease involved in fibrinolysis, Coagulation, and inflammation. The regulation of FXII expression is largely unknown. Transforming growth Factor-β1 (TGF-β1) is a multifunctional cytokine that has been linked to several pathological processes, including tissue fibrosis by modulating procoagulant and fibrinolytic activities. This study investigated whether TGF-β1 may regulate FXII expression in human lung fibroblasts. Treatment of human lung fibroblasts with TGF-β1 resulted in a time-dependent increase in FXII production, activation of p44/42, p38, JNK, and Akt, and phosphorylation and translocation into the nucleus of Smad3. However, TGF-β1-induced FXII expression was repressed only by the JNK inhibitor and JNK and Smad3 antisense oligonucleotides but not by MEK, p38, or phosphoinositide 3-kinase blockers. JNK inhibition had no effect on TGF-β1-induced Smad3 phosphorylation, association with Smad4, and its translocation into the nucleus but strongly suppressed Smad3-DNA complex formation. FXII promoter analysis revealed that the −299/+1 region was sufficient for TGF-β1 to induce FXII expression. Sequence analysis of this region detected a potential Smad-binding element at position −272/−269 (SBE-(−272/−269)). Chromatin immunoprecipitation and streptavidin pulldown assays demonstrated TGF-β1-dependent Smad3 binding to SBE-(−272/−269). Mutation or deletion of SBE-(−272/−269) substantially reduced TGF-β1-mediated activation of the FXII promoter. Clinical relevance was demonstrated by elevated FXII levels and its co-localization with fibroblasts in the lungs of patients with acute respiratory distress syndrome. Our results show that JNK/Smad3 pathway plays a critical role in TGF-β1-induced FXII expression in human lung fibroblasts and implicate its possible involvement in pathological conditions characterized by elevated TGF-β1 levels.
Bob Siegerink - One of the best experts on this subject based on the ideXlab platform.
-
Coagulation Factor XII xi and viii activity levels and secondary events after first ischemic stroke
Journal of Thrombosis and Haemostasis, 2020Co-Authors: Jessica L Rohmann, Shufan Huo, Pia S Sperber, Sophie K Piper, Frits R Rosendaal, Peter U Heuschmann, Matthias Endres, Thomas G Liman, Bob SiegerinkAbstract:Background Though risk for recurrent vascular events is high following ischemic stroke, little knowledge about risk Factors for secondary events post-stroke exists. Objectives Coagulation Factors XII, XI, and VIII (FXII, FXI, and FVIII) have been implicated in first thrombotic events, and our aim was to estimate their effects on vascular outcomes within 3 years after first stroke. Patients/methods In the Prospective Cohort with Incident Stroke Berlin (PROSCIS-B) study, we followed participants aged 18 and older for 3 years after first mild to moderate ischemic stroke event or until occurrence of recurrent stroke, myocardial infarction, or all-cause mortality. We compared high Coagulation Factor activity levels to normal and low levels and also analyzed activities as continuous variables. We used Cox proportional hazards models adjusted for age, sex, and cardiovascular risk Factors to estimate hazard ratios (HRs) for the combined endpoint. Results In total, 94 events occurred in 576 included participants, resulting in an absolute rate of 6.6 events per 100 person-years. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR = 2.05, 95% confidence interval [CI] 1.28-3.29). High FXI activity was also associated with a higher hazard (HR = 1.80, 95% CI 1.09-2.98), though high FXII activity was not (HR = 0.86, 95% CI 0.49-1.51). Continuous analyses yielded similar results. Conclusions In our study of mild to moderate ischemic stroke patients, high activity levels of FXI and FVIII but not FXII were associated with worse vascular outcomes in the 3-year period after first ischemic stroke.
-
Coagulation Factor XII xi and viii activity levels and secondary events after first ischemic stroke
medRxiv, 2019Co-Authors: Jessica L Rohmann, Shufan Huo, Pia S Sperber, Sophie K Piper, Frits R Rosendaal, Peter U Heuschmann, Matthias Endres, Thomas G Liman, Bob SiegerinkAbstract:Abstract Background and Purpose Though risk for recurrent vascular events is high following ischemic stroke, little is known about risk Factors for secondary events post-stroke. The Coagulation Factors XII, XI, and VII (FXII, FXI, and FVIII) have already been implicated in first thrombotic events, and our aim was to estimate their effects on vascular outcomes within 3 years after first stroke. Methods In the PROSpective Cohort with Incident Stroke Berlin (PROSCIS-B) study, we followed participants aged 18 and older for three years after first mild to moderate ischemic stroke event or until occurrence of recurrent stroke, myocardial infarction or all-cause mortality (combined endpoint). High Coagulation Factor activity levels were compared to normal and low levels, and activities were also analyzed as continuous variables. We used Cox proportional hazards models adjusted for age, sex, and cardiovascular risk Factors to estimate hazard ratios (HRs) for the combined endpoint. Results In total, 92 events occurred in 570 included participants, resulting in an absolute rate of 6.6 events per 100 person-years. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR=2.05, 95%CI 1.28-3.29). High FXI activity was also associated with an increased risk (HR=1.80, 95%CI 1.09-2.98). Contrarily, high FXII activity was not associated with the combined endpoint (HR=0.86, 95%CI 0.49-1.51). Continuous analyses per standard deviation of each biomarker yielded similar results. Conclusions In our study of mild to moderate ischemic stroke patients, high activity levels of FXI and FVIII but not FXII were associated with worse vascular outcomes in the three-year period after first ischemic stroke. This is of special interest in light of the ongoing trials of antithrombotic treatments targeting FXI.