Lukas Hobohm
University of Mainz
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Publication
Featured researches published by Lukas Hobohm.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2014
Sherin Alias; Bassam Redwan; Adelheid Panzenboeck; Max P. Winter; Uwe Schubert; Robert Voswinckel; Maria K. Frey; Johannes Jakowitsch; Arman Alimohammadi; Lukas Hobohm; Andreas Mangold; Helga Bergmeister; Maria Sibilia; Erwin F. Wagner; Eckhard Mayer; Walter Klepetko; Thomas J. Hoelzenbein; Klaus T. Preissner; Irene M. Lang
Objective— Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results— Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions— In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis. # Significance {#article-title-44}Objective—Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results—Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions—In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.
Blood | 2017
Saravanan Subramaniam; Kerstin Jurk; Lukas Hobohm; Sven Jäckel; Mona Saffarzadeh; Kathrin Schwierczek; Philip Wenzel; Florian Länger; Christoph Reinhardt; Wolfram Ruf
Expanding evidence indicates multiple interactions between the hemostatic system and innate immunity, and the coagulation and complement cascades. Here we show in a tissue factor (TF)-dependent model of flow restriction-induced venous thrombosis that complement factors make distinct contributions to platelet activation and fibrin deposition. Complement factor 3 (C3) deficiency causes prolonged bleeding, reduced thrombus incidence, thrombus size, fibrin and platelet deposition in the ligated inferior vena cava, and diminished platelet activation in vitro. Initial fibrin deposition at the vessel wall over 6 hours in this model was dependent on protein disulfide isomerase (PDI) and TF expression by myeloid cells, but did not require neutrophil extracellular trap formation involving peptidyl arginine deiminase 4. In contrast to C3-/- mice, C5-deficient mice had no apparent defect in platelet activation in vitro, and vessel wall platelet deposition and initial hemostasis in vivo. However, fibrin formation, the exposure of negatively charged phosphatidylserine (PS) on adherent leukocytes, and clot burden after 48 hours were significantly reduced in C5-/- mice compared with wild-type controls. These results delineate that C3 plays specific roles in platelet activation independent of formation of the terminal complement complex and provide in vivo evidence for contributions of complement-dependent membrane perturbations to prothrombotic TF activation on myeloid cells.
European Respiratory Journal | 2016
Lukas Hobohm; Kristian Hellenkamp; Gerd Hasenfuß; Thomas Münzel; Stavros Konstantinides; Mareike Lankeit
We compared the prognostic performance of the 2014 European Society of Cardiology (ESC) risk stratification algorithm with the previous 2008 ESC algorithm, the Bova score and the modified FAST score (based on a positive heart-type fatty acid-binding protein (H-FABP) test, syncope and tachycardia, modified using high-sensitivity troponin T instead of H-FABP) in 388 normotensive pulmonary embolism patients included in a single-centre cohort study. Overall, 25 patients (6.4%) had an adverse 30-day outcome. Regardless of the score or algorithm used, the rate of an adverse outcome was highest in the intermediate-high-risk classes, while all patients classified as low-risk had a favourable outcome (no pulmonary embolism-related deaths, 0–1.4% adverse outcome). The area under the curve for predicting an adverse outcome was higher for the 2014 ESC algorithm (0.76, 95% CI 0.68–0.84) compared with the 2008 ESC algorithm (0.65, 95% CI 0.56–0.73) and highest for the modified FAST score (0.82, 95% CI 0.75–0.89). Patients classified as intermediate-high-risk by the 2014 ESC algorithm had a 8.9-fold increased risk for an adverse outcome (3.2–24.2, p<0.001 compared with intermediate-low- and low-risk patients), while the highest OR was observed for a modified FAST score ≥3 points (OR 15.9, 95% CI 5.3–47.6, p<0.001). The 2014 ESC algorithm improves risk stratification of not-high-risk pulmonary embolism compared with the 2008 ESC algorithm. All scores and algorithms accurately identified low-risk patients, while the modified FAST score appears more suitable to identify intermediate-high-risk patients. 2014 ESC guideline algorithm improves risk stratification of not-high-risk PE compared with 2008 ESC algorithm http://ow.ly/UT0K6
Thrombosis and Haemostasis | 2017
Magdalena L. Bochenek; Nico Rosinus; Mareike Lankeit; Lukas Hobohm; Felix Bremmer; Eva Schütz; Frederikus A. Klok; Sven Horke; Christoph B. Wiedenroth; Thomas Münzel; Irene Lang; Eckhard Mayer; Stavros Konstantinides; Katrin Schäfer
The pathomechanisms underlying the development of thrombofibrotic pulmonary artery occlusions in Chronic Thromboembolic Pulmonary Hypertension (CTEPH) are largely unknown. The aim of this study was to allocate distinct cellular processes playing a role in thrombus resolution, such as inflammation, hypoxia, proliferation, apoptosis and angiogenesis, to different stages of thrombofibrotic remodelling. A total of 182 pulmonary endarterectomy (PEA) specimens were collected from 31 CTEPH patients. To facilitate co-localisation, Tissue MicroArrays were prepared and processed for (immuno)-histochemistry and confocal fluorescence microscopy. Murine venous thrombus formation and resolution was examined after inferior vena cava ligation. PEA tissues exhibited five morphologically distinct regions predominantly consisting of either fibrin-, erythrocyte- or extracellular matrix-rich thrombus, myofibroblasts, vessels or fibrotic tissue, and were found to resemble chronological stages of thrombus resolution in mice. Cellularity was highest in vessel-rich regions, and numerous cells were strongly positive for HIF1α or HIF2α as well as markers of activated VEGF signalling, including endothelial nitric oxide synthase. On the other hand, negative regulators of angiogenic growth factor signalling and reactive oxygen species were also highly expressed. Immune cells, primarily macrophages of the M2 subtype and CD117 haematopoietic progenitors were detected and highest in vascularised regions. Our findings demonstrate the simultaneous presence of different stages of thrombus organisation and suggest that hypoxia-induced endothelial, mesenchymal and immune cell activation may contribute to thrombofibrosis in CTEPH. This systematic histological characterisation of the material obstructing pulmonary vessels in CTEPH may provide a valuable basis for further studies aimed at determining causal factors underlying this disease.
Oxidative Medicine and Cellular Longevity | 2018
Moritz Brandt; Eleni Giokoglu; Venkata Garlapati; Madgalena L. Bochenek; Michael Molitor; Lukas Hobohm; Tanja Schönfelder; Thomas Münzel; Sabine Kossmann; Susanne Karbach; Katrin Schäfer; Philip Wenzel
Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH.
European Respiratory Journal | 2018
Kristian Hellenkamp; Piotr Pruszczyk; David F. Jimenez; Anna Wyzgał; Deisy Barrios; Michał Ciurzyński; Raquel Morillo; Lukas Hobohm; Karsten Keller; Katarzyna Kurnicka; Maciej Kostrubiec; Rolf Wachter; Gerd Hasenfuß; Stavros Konstantinides; Mareike Lankeit
To externally validate the prognostic impact of copeptin, either alone or integrated in risk stratification models, in pulmonary embolism (PE), we performed a post hoc analysis of 843 normotensive PE patients prospectively included in three European cohorts. Within the first 30 days, 21 patients (2.5%, 95% CI 1.5–3.8) had an adverse outcome and 12 (1.4%, 95% CI 0.7–2.5) died due to PE. Patients with copeptin ≥24 pmol·L−1 had a 6.3-fold increased risk for an adverse outcome (95% CI 2.6–15.5, p<0.001) and a 7.6-fold increased risk for PE-related death (95% CI 2.3–25.6, p=0.001). Risk classification according to the 2014 European Society of Cardiology (ESC) guideline algorithm identified 248 intermediate-high-risk patients (29.4%) with 5.6% (95% CI 3.1–9.3) at risk of adverse outcomes. A stepwise biomarker-based risk assessment strategy (based on high-sensitivity troponin T, N-terminal pro-brain natriuretic peptide and copeptin) identified 123 intermediate-high-risk patients (14.6%) with 8.9% (95% CI 4.5–15.4) at risk of adverse outcomes. The identification of patients at higher risk was even better when copeptin was measured on top of the 2014 ESC algorithm in intermediate-high-risk patients (adverse outcome OR 11.1, 95% CI 4.6–27.1, p<0.001; and PE-related death OR 13.5, 95% CI 4.2–43.6, p<0.001; highest risk group versus all other risk groups). This identified 85 patients (10.1%) with 12.9% (95% CI 6.6–22.0) at risk of adverse outcomes and 8.2% (95% CI 3.4–16.2) at risk of PE-related deaths. Copeptin improves risk stratification of normotensive PE patients, especially when identifying patients with an increased risk of an adverse outcome. Copeptin improves risk stratification of normotensive patients with pulmonary embolism http://ow.ly/8E3P30jtvym
Arteriosclerosis, Thrombosis, and Vascular Biology | 2014
Sherin Alias; Bassam Redwan; Adelheid Panzenböck; Max P. Winter; Uwe Schubert; Robert Voswinckel; Maria K. Frey; Johannes Jakowitsch; Arman Alimohammadi; Lukas Hobohm; Andreas Mangold; Helga Bergmeister; Maria Sibilia; Erwin F. Wagner; Eckhard Mayer; Walter Klepetko; Thomas Hölzenbein; Klaus T. Preissner; Irene M. Lang
Objective— Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results— Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions— In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis. # Significance {#article-title-44}Objective—Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results—Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions—In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2014
Sherin Alias; Bassam Redwan; Adelheid Panzenböck; Max P. Winter; Uwe Schubert; Robert Voswinckel; Maria K. Frey; Johannes Jakowitsch; Arman Alimohammadi; Lukas Hobohm; Andreas Mangold; Helga Bergmeister; Maria Sibilia; Erwin F. Wagner; Eckhard Mayer; Walter Klepetko; Thomas J. Hölzenbein; Klaus T. Preissner; Irene M. Lang
Objective— Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results— Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions— In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis. # Significance {#article-title-44}Objective—Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results—Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions—In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.
American Journal of Cardiology | 2017
Karsten Keller; Ralph Stephan von Bardeleben; Mir Abolfazl Ostad; Lukas Hobohm; Thomas Münzel; Stavros Konstantinides; Mareike Lankeit
Journal of Heart and Lung Transplantation | 2017
Mareike Lankeit; Valentin Krieg; Lukas Hobohm; Sebastian Kölmel; Christoph Liebetrau; Stavros Konstantinides; Christian W. Hamm; Eckhard Mayer; Christoph B. Wiedenroth; Stefan Guth