@article{LugerHohmannNiemannetal.2015,
  author    = {Luger, Sebastian and Hohmann, Carina and Niemann, Daniela and Kraft, Peter and Gunreben, Ignaz and Neumann-Haefelin, Tobias and Kleinschnitz, Christoph and Steinmetz, Helmuth and Foerch, Christian and Pfeilschifter, Waltraud},
  title     = {Adherence to oral anticoagulant therapy in secondary stroke prevention - impact of the novel oral anticoagulants},
  series = {Patient Preference and Adherence},
  volume    = {9},
  journal   = {Patient Preference and Adherence},
  doi       = {10.2147/PPA.S88994},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144477},
  pages     = {1695-1705},
  year      = {2015},
  abstract  = {Background: Oral anticoagulant therapy (OAT) potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA) have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC) have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention. Methods: All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients' adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT. Results: In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3\% (n=209). A total of 92\% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9\%; NOAC, 74.8\%; P=0.243) with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence. Conclusion: One-year adherence to OAT after stroke is strong (>90\%) and patients who switch therapy most commonly switch toward another OAT. The 1-year adherence rates to VKA and NOAC in secondary stroke prevention do not differ significantly between both therapeutic strategies.},
  language  = {en}
}
@article{SchuhmannLanghauserKraftetal.2017,
  author    = {Schuhmann, Michael K. and Langhauser, Friederike and Kraft, Peter and Kleinschnitz, Christoph},
  title     = {B cells do not have a major pathophysiologic role in acute ischemic stroke in mice},
  series = {Journal of Neuroinflammation},
  volume    = {14},
  journal   = {Journal of Neuroinflammation},
  number    = {112},
  doi       = {10.1186/s12974-017-0890-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158155},
  year      = {2017},
  abstract  = {Background Lymphocytes have been shown to play an important role in the pathophysiology of acute ischemic stroke, but the properties of B cells remain controversial. The aim of this study was to unravel the role of B cells during acute cerebral ischemia using pharmacologic B cell depletion, B cell transgenic mice, and adoptive B cell transfer experiments. Methods Transient middle cerebral artery occlusion (60 min) was induced in wild-type mice treated with an anti-CD20 antibody 24 h before stroke onset, JHD\(^{-/-}\) mice and Rag1\(^{-/-}\) mice 24 h after adoptive B cell transfer. Stroke outcome was assessed at days 1 and 3. Infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections, and neurological scores were evaluated. The local inflammatory response was determined by real-time PCR and immunohistochemistry. Apoptosis was analyzed by TUNEL staining, and astrocyte activation was revealed using immunohistochemistry and Western blot. Results Pharmacologic depletion of B cells did not influence infarct volumes and functional outcome at day 1 after stroke. Additionally, lack of circulating B cells in JHD\(^{-/-}\) mice also failed to influence stroke outcome at days 1 and 3. Furthermore, reconstitution of Rag1\(^{-/-}\) mice with B cells had no influence on infarct volumes. Conclusion Targeting B cells in experimental stroke did not influence lesion volume and functional outcome during the acute phase. Our findings argue against a major pathophysiologic role of B cells during acute ischemic stroke.},
  language  = {en}
}
@article{SchuhmannGuthmannStolletal.2017,
  author    = {Schuhmann, Michael K. and Guthmann, Josua and Stoll, Guido and Nieswandt, Bernhard and Kraft, Peter and Kleinschnitz, Christoph},
  title     = {Blocking of platelet glycoprotein receptor Ib reduces "thrombo-inflammation" in mice with acute ischemic stroke},
  series = {Journal of Neuroinflammation},
  volume    = {14},
  journal   = {Journal of Neuroinflammation},
  number    = {18},
  doi       = {10.1186/s12974-017-0792-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157582},
  year      = {2017},
  abstract  = {Background: Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation. Methods: Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO. Results: Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls. Conclusion: In acute ischemic stroke, thrombus formation and inflammation are closely intertwined ("thrombo-inflammation"). Blocking of platelet GPIb can ameliorate thrombo-inflammation.},
  language  = {en}
}
@article{GoebelPankratzAsaridouetal.2016,
  author    = {G{\"o}bel, Kerstin and Pankratz, Susann and Asaridou, Chloi-Magdalini and Herrmann, Alexander M. and Bittner, Stefan and Merker, Monika and Ruck, Tobias and Glumm, Sarah and Langhauser, Friederike and Kraft, Peter and Krug, Thorsten F. and Breuer, Johanna and Herold, Martin and Gross, Catharina C. and Beckmann, Denise and Korb-Pap, Adelheid and Schuhmann, Michael K. and Kuerten, Stefanie and Mitroulis, Ioannis and Ruppert, Clemens and Nolte, Marc W. and Panousis, Con and Klotz, Luisa and Kehrel, Beate and Korn, Thomas and Langer, Harald F. and Pap, Thomas and Nieswandt, Bernhard and Wiendl, Heinz and Chavakis, Triantafyllos and Kleinschnitz, Christoph and Meuth, Sven G.},
  title     = {Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  number    = {11626},
  doi       = {10.1038/ncomms11626},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165503},
  year      = {2016},
  abstract  = {Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.},
  language  = {en}
}
@article{KraftDrechslerGunrebenetal.2015,
  author    = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph},
  title     = {Case-control study of platelet glycoprotein receptor Ib and IIb/IIIa expression in patients with acute and chronic cerebrovascular disease},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0119810},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148806},
  pages     = {e0119810},
  year      = {2015},
  abstract  = {Background Animal models have been instrumental in defining thrombus formation, including the role of platelet surface glycoprotein (GP) receptors, in acute ischemic stroke (AIS). However, the involvement of GP receptors in human ischemic stroke pathophysiology and their utility as biomarkers for ischemic stroke risk and severity requires elucidation. Aims To determine whether platelet GPIb and GPIIb/IIIa receptors are differentially expressed in patients with AIS and chronic cerebrovascular disease (CCD) compared with healthy volunteers (HV) and to identify predictors of GPIb and GPIIb/IIIa expression. Methods This was a case-control study of 116 patients with AIS or transient ischemic attack (TIA), 117 patients with CCD, and 104 HV who were enrolled at our University hospital from 2010 to 2013. Blood sampling was performed once in the CCD and HV groups, and at several time points in patients with AIS or TIA. Linear regression and analysis of variance were used to analyze correlations between platelet GPIb and GPIIb/IIIa receptor numbers and demographic and clinical parameters. Results GPIb and GPIIb/IIIa receptor numbers did not significantly differ between the AIS, CCD, and HV groups. GPIb receptor expression level correlated significantly with the magnitude of GPIIb/IIIa receptor expression and the neutrophil count. In contrast, GPIIb/IIIa receptor numbers were not associated with peripheral immune-cell sub-population counts. Creactive protein was an independent predictor of GPIIb/IIIa (not GPIb) receptor numbers. Conclusions Platelet GPIb and GPIIb/IIIa receptor numbers did not distinguish between patient or control groups in this study, negating their potential use as a biomarker for predicting stroke risk.},
  language  = {en}
}
@article{HohnmannMillesSchinkeetal.2014,
  author    = {Hohnmann, Christopher and Milles, Bianca and Schinke, Michael and Schroeter, Michael and Ulzheimer, Jochen and Kraft, Peter and Kleinschnitz, Christoph and Lehmann, Paul V. and Kuerten, Stefanie},
  title     = {Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood},
  series = {Acta Neuropathologica Communications},
  volume    = {2},
  journal   = {Acta Neuropathologica Communications},
  number    = {138},
  doi       = {10.1186/s40478-014-0138-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126124},
  year      = {2014},
  abstract  = {Introduction B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Results Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5\%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40\%) with a pattern II and three of 14 patients (21.4\%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95\% confidence interval 1.87-19.77). Conclusions Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.},
  language  = {en}
}
@article{HohmannMillesSchinkeetal.2014,
  author    = {Hohmann, Christopher and Milles, Bianca and Schinke, Michael and Schroeter, Michael and Ulzheimer, Jochen and Kraft, Peter and Kleinschnitz, Christoph and Lehmann, Paul V. and Kuerten, Stefanie},
  title     = {Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood},
  series = {Acta Neuropathologica Communications},
  volume    = {2},
  journal   = {Acta Neuropathologica Communications},
  number    = {138},
  issn      = {2051-5960},
  doi       = {10.1186/s40478-014-0138-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120580},
  year      = {2014},
  abstract  = {INTRODUCTION: B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). RESULTS: Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5\%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40\%) with a pattern II and three of 14 patients (21.4\%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95\% confidence interval 1.87-19.77). CONCLUSIONS: Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.},
  language  = {en}
}
@article{KraftSchuhmann2022,
  author    = {Kraft, Peter and Schuhmann, Michael K.},
  title     = {Cellular and molecular targets in acute ischemic stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {19},
  issn      = {1422-0067},
  doi       = {10.3390/ijms231911097},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288294},
  year      = {2022},
  abstract  = {No abstract available},
  language  = {en}
}
@article{KraftDrechslerSchuhmannetal.2015,
  author    = {Kraft, Peter and Drechsler, Christiane and Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph},
  title     = {Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study},
  series = {International Journal of Molecular Science},
  volume    = {16},
  journal   = {International Journal of Molecular Science},
  number    = {10},
  doi       = {10.3390/ijms161025433},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126319},
  pages     = {25433-25449},
  year      = {2015},
  abstract  = {Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital W{\"u}rzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies.},
  language  = {en}
}
@article{KraftBenzAustinatetal.2010,
  author    = {Kraft, Peter and Benz, Peter Michael and Austinat, Madeleine and Brede, Marc Elmar and Schuh, Kai and Walter, Ulrich and Stoll, Guido and Kleinschnitz, Christoph},
  title     = {Deficiency of Vasodilator-Stimulated Phosphoprotein (VASP) Increases Blood-Brain-Barrier Damage and Edema Formation after Ischemic Stroke in Mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68522},
  year      = {2010},
  abstract  = {Background: Stroke-induced brain edema formation is a frequent cause of secondary infarct growth and deterioration of neurological function. The molecular mechanisms underlying edema formation after stroke are largely unknown. Vasodilator-stimulated phosphoprotein (VASP) is an important regulator of actin dynamics and stabilizes endothelial barriers through interaction with cell-cell contacts and focal adhesion sites. Hypoxia has been shown to foster vascular leakage by downregulation of VASP in vitro but the significance of VASP for regulating vascular permeability in the hypoxic brain in vivo awaits clarification. Methodology/Principal Findings: Focal cerebral ischemia was induced in Vasp2/2 mice and wild-type (WT) littermates by transient middle cerebral artery occlusion (tMCAO). Evan's Blue tracer was applied to visualize the extent of blood-brainbarrier (BBB) damage. Brain edema formation and infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices. Both mouse groups were carefully controlled for anatomical and physiological parameters relevant for edema formation and stroke outcome. BBB damage (p,0.05) and edema volumes (1.7 mm360.5 mm3 versus 0.8 mm360.4 mm3; p,0.0001) were significantly enhanced in Vasp2/2 mice compared to controls on day 1 after tMCAO. This was accompanied by a significant increase in infarct size (56.1 mm3617.3 mm3 versus 39.3 mm3610.7 mm3, respectively; p,0.01) and a non significant trend (p.0.05) towards worse neurological outcomes. Conclusion: Our study identifies VASP as critical regulator of BBB maintenance during acute ischemic stroke. Therapeutic modulation of VASP or VASP-dependent signalling pathways could become a novel strategy to combat excessive edema formation in ischemic brain damage.},
  subject      = {Vasodilatator-stimuliertes Phosphoprotein},
  language  = {en}
}
@article{BellutBieberKraftetal.2023,
  author    = {Bellut, Maximilian and Bieber, Michael and Kraft, Peter and Weber, Alexander N. R. and Stoll, Guido and Schuhmann, Michael K.},
  title     = {Delayed NLRP3 inflammasome inhibition ameliorates subacute stroke progression in mice},
  series = {Journal of Neuroinflammation},
  volume    = {20},
  journal   = {Journal of Neuroinflammation},
  number    = {1},
  doi       = {10.1186/s12974-022-02674-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300599},
  year      = {2023},
  abstract  = {Background Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke. Methods Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO. Results Infarct sizes on day 7 after tMCAO decreased about 35\% after delayed and about 60\% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis. Conclusions Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome—even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke.},
  language  = {en}
}
@phdthesis{Kraft2008,
  author    = {Kraft, Peter},
  title     = {Einfluß des Tumormikromilieus auf die Akkumulation des Hypoxia-inducible Factor-1 alpha (HIF-1 alpha) in humanen Tumorzellen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-27135},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {Die Transduktionsfaktoruntereinheit HIF-1alpha ist der zentrale Sauerstoffsensor f{\"u}r S{\"a}ugerzellen aller Art. Er ist in der Lage durch Steuerung der Transkription entsprechender Gene auf die Zellproliferation, verschiedene Transportvorg{\"a}nge, die Angiogenese, die Glykolyse und andere Vorg{\"a}nge Einfluß zu nehmen. Zahlreiche Studien belegen den Zusammenhang zwischen HIF-1alpha-{\"U}berexpression in soliden Tumoren und Verk{\"u}rzung der {\"U}berlebens- bzw. der rezidivfreien Zeit. Schon lange ist die Assoziation von Tumorhypoxie mit der Verschlechterung der Prognose der Erkrankung bekannt. Die Trennung der hypoxischen Srahlenresistenz von der pro-proliferativen und pro-metastatischen Potenz von HIF-1alpha als Ursache der Prognoseverschlechterung von tumorkranken Patienten ist derzeit nicht m{\"o}glich. Die vorliegende Arbeit zeigt anhand zweier etablierter humaner Tumorzellinien, daß Faktoren des Tumormikromilieus in der Lage sein k{\"o}nnen, die HIF-1alpha-Expression zu modulieren. Hypoxie war stets eine Grundvoraussetzung f{\"u}r die Messung erh{\"o}hter HIF-1alpha-Spiegel. Jedoch waren ann{\"a}hernd normale Glukosespiegel des Tumormikromilieus f{\"u}r eine nennenswerte HIF-1alpha-{\"U}berexpression erforderlich. Dies k{\"o}nnte erkl{\"a}ren, warum immunhistochemische Schnitte von HIF-1alpha und von exogenen Hypoxiemarkern bez{\"u}glich der angef{\"a}rbten Areale differieren. Sowohl die mangelnde Spezifit{\"a}t der HIF-1alpha-Expression f{\"u}r Hypoxie, als auch die f{\"u}r klinische Routinearbeiten ung{\"u}nstige Kinetik des endogenen Hypoxiemarkers HIF-1alpha, lassen an seiner praktischen Einf{\"u}hrung in der Klinik zweifeln. Da noch kein endogener Hypoxiemarker gefunden werden konnte, der spezifisch bei Hypoxie akkumulieren w{\"u}rde, und dar{\"u}ber hinaus alle bekannten endogenen Hypoxiemarker bei Sauerstoffmangel unterschiedlich reagieren, scheint es derzeit am sinnvollsten zu sein, neben der Kombination von verschiedenen Markern außerdem andere Faktoren, wie die Vaskularisierungsdichte zu bestimmen. Die Tatsache, daß nicht alle hypoxischen Zellen HIF-1alpha exprimieren, und die, daß aufgrund der nicht-hypoxischen Aktivierung von HIF-1alpha unter Umst{\"a}nden auch nicht hypoxische Zellen gesteigerte HIF-1alpha-Spiegel aufweisen, k{\"o}nnte ein therapeutisches Eingreifen auf Ebene von HIF-1alpha - als vermeintlich tumorspezifische Therapieform - in Frage stellen. Die Ergebnisse zahlreicher Studien zeigen deutlich, daß HIF-1alpha weder hypoxiespezifisch noch tumorspezifisch in der Zelle akkumuliert. Die Zukunft wird zeigen, ob es eine neue Substanzklasse der „HIF-1-Inhibitoren" geben wird. Derzeit laufen mehrere klinische Studien zur Evaluierung denkbarer Substanzen.},
  subject      = {Hypoxie},
  language  = {de}
}
@article{JirůHillmannGabrielSchuleretal.2022,
  author    = {J{\´i}rů-Hillmann, Steffi and Gabriel, Katharina M. A. and Schuler, Michael and Wiedmann, Silke and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Soda, Hassan and Rascher, Alexandra and Benesch, Sonka and Kraft, Peter and Pfau, Mathias and Stenzel, Joachim and von Nippold, Karin and Benghebrid, Mohamed and Schulte, Kerstin and Meinck, Ralf and Volkmann, Jens and Haeusler, Karl Georg and Heuschmann, Peter U.},
  title     = {Experiences of family caregivers 3-months after stroke: results of the prospective trans-regional network for stroke intervention with telemedicine registry (TRANSIT-Stroke)},
  series = {BMC Geriatrics},
  volume    = {22},
  journal   = {BMC Geriatrics},
  doi       = {10.1186/s12877-022-02919-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313330},
  year      = {2022},
  abstract  = {Background Long-term support of stroke patients living at home is often delivered by family caregivers (FC). We identified characteristics of stroke patients being associated with receiving care by a FC 3-months (3 M) after stroke, assessed positive and negative experiences and individual burden of FC caring for stroke patients and determined factors associated with caregiving experiences and burden of FC 3 M after stroke. Methods Data were collected within TRANSIT-Stroke, a regional telemedical stroke-network comprising 12 hospitals in Germany. Patients with stroke/TIA providing informed consent were followed up 3 M after the index event. The postal patient-questionnaire was accompanied by an anonymous questionnaire for FC comprising information on positive and negative experiences of FC as well as on burden of caregiving operationalized by the Caregiver Reaction Assessment and a self-rated burden-scale, respectively. Multivariable logistic and linear regression analyses were performed. Results Between 01/2016 and 06/2019, 3532 patients provided baseline and 3 M-follow-up- data and 1044 FC responded to questionnaires regarding positive and negative caregiving experiences and caregiving burden. 74.4\% of FC were older than 55 years, 70.1\% were women and 67.5\% were spouses. Older age, diabetes and lower Barthel-Index in patients were significantly associated with a higher probability of receiving care by a FC at 3 M. Positive experiences of FC comprised the importance (81.5\%) and the privilege (70.0\%) of caring for their relative; negative experiences of FC included financial difficulties associated with caregiving (20.4\%). Median overall self-rated burden was 30 (IQR: 0-50; range 0-100). Older age of stroke patients was associated with a lower caregiver burden, whereas younger age of FC led to higher burden. More than half of the stroke patients in whom a FC questionnaire was completed did self-report that they are not being cared by a FC. This stroke patient group tended to be younger, more often male with less severe stroke and less comorbidities who lived more often with a partner. Conclusions The majority of caregivers wanted to care for their relatives but experienced burden at the same time. Elderly patients, patients with a lower Barthel Index at discharge and diabetes are at higher risk of needing care by a family caregiver. Trial registration The study was registered at "German Clinical Trial Register": DRKS00011696. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML\&TRIAL_ID=DRKS00011696},
  language  = {en}
}
@article{KraftFleischerWiedmannetal.2017,
  author    = {Kraft, Peter and Fleischer, Anna and Wiedmann, Silke and R{\"u}cker, Viktoria and Mackenrodt, Daniel and Morbach, Caroline and Malzahn, Uwe and Kleinschnitz, Christoph and St{\"o}rk, Stefan and Heuschmann, Peter U.},
  title     = {Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study},
  series = {BMC Neurology},
  volume    = {17},
  journal   = {BMC Neurology},
  number    = {159},
  doi       = {10.1186/s12883-017-0937-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158081},
  year      = {2017},
  abstract  = {Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital W{\"u}rzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95\% confidence intervals (95\% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95\% CI 0.71-0.89) to 0.93 (95\% CI 0.87-0.96), and κ from 0.39 (-95\% CI 0.14-0.92) to 0.79 (95\% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95\% CI 0.40-0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.},
  language  = {en}
}
@article{KleinschnitzGoebelMeuthetal.2014,
  author    = {Kleinschnitz, Christoph and G{\"o}bel, Kerstin and Meuth, Sven G. and Kraft, Peter},
  title     = {Glatiramer acetate does not protect from acute ischemic stroke in mice},
  doi       = {10.1186/2040-7378-6-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110528},
  year      = {2014},
  abstract  = {Background The role of the immune system in the pathophysiology of acute ischemic stroke is increasingly recognized. However, targeted treatment strategies to modulate immunological pathways in stroke are still lacking. Glatiramer acetate is a multifaceted immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. Experimental studies suggest that glatiramer acetate might also work in other neuroinflammatory or neurodegenerative diseases apart from multiple sclerosis. Findings We evaluated the efficacy of glatiramer acetate in a mouse model of brain ischemia/reperfusion injury. 60 min of transient middle cerebral artery occlusion was induced in male C57Bl/6 mice. Pretreatment with glatiramer acetate (3.5 mg/kg bodyweight) 30 min before the induction of stroke did not reduce lesion volumes or improve functional outcome on day 1. Conclusions Glatiramer acetate failed to protect from acute ischemic stroke in our hands. Further studies are needed to assess the true therapeutic potential of glatiramer acetate and related immunomodulators in brain ischemia.},
  language  = {en}
}
@article{EssigBabilonVollmuthetal.2021,
  author    = {Essig, Fabian and Babilon, Lilith and Vollmuth, Christoph and Kollikowski, Alexander M. and Pham, Mirko and Solymosi, L{\´a}szl{\´o} and Haeusler, Karl Georg and Kraft, Peter and Stoll, Guido and Schuhmann, Michael K.},
  title     = {High mobility group box 1 protein in cerebral thromboemboli},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {20},
  issn      = {1422-0067},
  doi       = {10.3390/ijms222011276},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265568},
  year      = {2021},
  abstract  = {High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7\% (IQR 0.6-6.2\%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.},
  language  = {en}
}
@article{HansenSeilerRumpfetal.2012,
  author    = {Hansen, Niels and Seiler, Carola and Rumpf, Julian and Kraft, Peter and Dlaske, Henry and Abele-Horn, Marianne and Muellges, Wolfgang},
  title     = {Human Tuberculous Meningitis Caused by \(Mycobacterium\) \(caprae\)},
  series = {Case Reports in Neurology},
  volume    = {4},
  journal   = {Case Reports in Neurology},
  number    = {1},
  doi       = {10.1159/000337299},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123425},
  pages     = {54-60},
  year      = {2012},
  abstract  = {INTRODUCTION: Tuberculous meningitis (TM) causes substantial morbidity and mortality in humans. Human TM has been known to be induced by bacteria from the Mycobacterium tuberculosis complex (MTBC), such as M. tuberculosis and M. bovis. CASE PRESENTATION: We describe a case of meningitis treated with fosfomycin, which showed partial effectiveness in an 80-year-old patient. After a lethal myocardial infarction, M. caprae (MC) was identified in cerebrospinal fluid culture. This isolated acid-fast organism was first identified as MTBC by MTBC-specific PCR (16S rDNA-PCR). Furthermore, species-specific identification of the isolate was done by gyrB PCR-restriction fragment length polymorphism analysis of a part of gyrB DNA. Colony morphology of the isolated MC strain showed dysgonic growth on Lowenstein-Jensen medium. The strain was susceptible to pyrazinamide (PZA). CONCLUSION: This isolated strain was convincingly identified as MC according to the phenotypic and genotypic characteristics and PZA sensitivity. This is the first report of MC causing TM.},
  language  = {en}
}
@article{KraftSchuhmannGarzetal.2017,
  author    = {Kraft, Peter and Schuhmann, Michael K. and Garz, Cornelia and Jandke, Solveig and Urlaub, Daniela and Mencl, Stine and Zernecke, Alma and Heinze, Hans-Jochen and Carare, Roxana O. and Kleinschnitz, Christoph and Schreiber, Stefanie},
  title     = {Hypercholesterolemia induced cerebral small vessel disease},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0182822},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170493},
  pages     = {e0182822},
  year      = {2017},
  abstract  = {Background While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr\(^{-/-}\) mouse model. Methods We used Ldlr\(^{-/-}\) mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr\(^{-/-}\) mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds. Results We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr\(^{-/-}\) mice compared to all other groups (P < 0.05). Ldlr\(^{-/-}\) animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr\(^{-/-}\) mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr\(^{-/-}\) mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions. Conclusions In Ldlr\(^{-/-}\) mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr\(^{-/-}\) mice appear to be an adequate animal model for research into CSVD.},
  language  = {en}
}
@article{SchuhmannGunrebenKleinschnitzetal.2016,
  author    = {Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph and Kraft, Peter},
  title     = {Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {17},
  journal   = {International Journal of Molecular Sciences},
  number    = {3},
  doi       = {10.3390/ijms17030298},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166206},
  pages     = {298},
  year      = {2016},
  abstract  = {Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke.},
  language  = {en}
}
@article{EssigKollikowskiPhametal.2020,
  author    = {Essig, Fabian and Kollikowski, Alexander M. and Pham, Mirko and Solymosi, L{\´a}szl{\´o} and Stoll, Guido and Haeusler, Karl Georg and Kraft, Peter and Schuhmann, Michael K.},
  title     = {Immunohistological analysis of neutrophils and neutrophil extracellular traps in human thrombemboli causing acute ischemic stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {19},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21197387},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236192},
  year      = {2020},
  abstract  = {Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity.},
  language  = {en}
}
@article{KraftDeMeyerKleinschnitz2012,
  author    = {Kraft, Peter and De Meyer, Simon F. and Kleinschnitz, Christoph},
  title     = {Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on 'Bleeding-Free Antithrombosis'},
  series = {Journal of Cerebral Blood Flow and Metabolism},
  volume    = {32},
  journal   = {Journal of Cerebral Blood Flow and Metabolism},
  number    = {10},
  doi       = {10.1038/jcbfm.2012.108},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126538},
  pages     = {1831-1840},
  year      = {2012},
  abstract  = {The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.},
  language  = {en}
}
@article{BellutPappBieberetal.2022,
  author    = {Bellut, Maximilian and Papp, Lena and Bieber, Michael and Kraft, Peter and Stoll, Guido and Schuhmann, Michael K.},
  title     = {NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in-vitro and protects blood-brain barrier integrity in murine stroke},
  series = {Cell Death \& Disease},
  volume    = {13},
  journal   = {Cell Death \& Disease},
  doi       = {10.1038/s41419-021-04379-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265693},
  year      = {2022},
  abstract  = {In ischemic stroke (IS) impairment of the blood-brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and-in good agreement with the in vitro results-MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC.},
  language  = {en}
}
@article{WolfBraunHainingetal.2016,
  author    = {Wolf, Karen and Braun, Attila and Haining, Elizabeth J. and Tseng, Yu-Lun and Kraft, Peter and Schuhmann, Michael K. and Gotru, Sanjeev K. and Chen, Wenchun and Hermanns, Heike M. and Stoll, Guido and Lesch, Klaus-Peter and Nieswandt, Bernhard},
  title     = {Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {1},
  doi       = {10.1371/journal.pone.0147664},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146399},
  pages     = {e0147664},
  year      = {2016},
  abstract  = {Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.},
  language  = {en}
}
@article{KleinschnitzGrundWingleretal.2010,
  author    = {Kleinschnitz, Christoph and Grund, Henrike and Wingler, Kirstin and Armitage, Melanie E. and Jones, Emma and Mittal, Manish and Barit, David and Schwarz, Tobias and Geis, Christian and Kraft, Peter and Barthel, Konstanze and Schuhmann, Michael K. and Herrmann, Alexander M. and Meuth, Sven G. and Stoll, Guido and Meurer, Sabine and Schrewe, Anja and Becker, Lore and Gailus-Durner, Valerie and Fuchs, Helmut and Klopstock, Thomas and de Angelis, Martin Hrabe and Jandeleit-Dahm, Karin and Shah, Ajay M. and Weissmann, Norbert and Schmidt, Harald H. H. W.},
  title     = {Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68416},
  year      = {2010},
  abstract  = {Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90\% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.},
  subject      = {Schlaganfall},
  language  = {en}
}
@article{HeuschmannMontellanoUngethuemetal.2021,
  author    = {Heuschmann, Peter U. and Montellano, Felipe A. and Ungeth{\"u}m, Kathrin and R{\"u}cker, Viktoria and Wiedmann, Silke and Mackenrodt, Daniel and Quilitzsch, Anika and Ludwig, Timo and Kraft, Peter and Albert, Judith and Morbach, Caroline and Frantz, Stefan and St{\"o}rk, Stefan and Haeusler, Karl Georg and Kleinschnitz, Christoph},
  title     = {Prevalence and determinants of systolic and diastolic cardiac dysfunction and heart failure in acute ischemic stroke patients: The SICFAIL study},
  series = {ESC Heart Failure},
  volume    = {8},
  journal   = {ESC Heart Failure},
  number    = {2},
  doi       = {10.1002/ehf2.13145},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225656},
  pages     = {1117-1129},
  year      = {2021},
  abstract  = {Aims Ischaemic stroke (IS) might induce alterations of cardiac function. Prospective data on frequency of cardiac dysfunction and heart failure (HF) after IS are lacking. We assessed prevalence and determinants of diastolic dysfunction (DD), systolic dysfunction (SD), and HF in patients with acute IS. Methods and results The Stroke-Induced Cardiac FAILure in mice and men (SICFAIL) study is a prospective, hospital-based cohort study. Patients with IS underwent a comprehensive assessment of cardiac function in the acute phase (median 4 days after IS) including clinical examination, standardized transthoracic echocardiography by expert sonographers, and determination of blood-based biomarkers. Information on demographics, lifestyle, risk factors, symptoms suggestive of HF, and medical history was collected by a standardized personal interview. Applying current guidelines, cardiac dysfunction was classified based on echocardiographic criteria into SD (left ventricular ejection fraction < 52\% in men or <54\% in women) and DD (≥3 signs of DD in patients without SD). Clinically overt HF was classified into HF with reduced, mid-range, or preserved ejection fraction. Between January 2014 and February 2017, 696 IS patients were enrolled. Of them, patients with sufficient echocardiographic data on SD were included in the analyses {n = 644 patients [median age 71 years (interquartile range 60-78), 61.5\% male]}. In these patients, full assessment of DD was feasible in 549 patients without SD (94\%). Prevalence of cardiac dysfunction and HF was as follows: SD 9.6\% [95\% confidence interval (CI) 7.6-12.2\%]; DD in patients without SD 23.3\% (95\% CI 20.0-27.0\%); and clinically overt HF 5.4\% (95\% CI 3.9-7.5\%) with subcategories of HF with preserved ejection fraction 4.35\%, HF with mid-range ejection fraction 0.31\%, and HF with reduced ejection fraction 0.78\%. In multivariable analysis, SD and fulfilment of HF criteria were associated with history of coronary heart disease [SD: odds ratio (OR) 3.87, 95\% CI 1.93-7.75, P = 0.0001; HF: OR 2.29, 95\% CI 1.04-5.05, P = 0.0406] and high-sensitive troponin T at baseline (SD: OR 1.78, 95\% CI 1.31-2.42, P = 0.0003; HF: OR 1.66, 95\% CI 1.17-2.33, P = 0.004); DD was associated with older age (OR 1.08, 95\% CI 1.05-1.11, P < 0.0001) and treated hypertension vs. no hypertension (OR 2.84, 95\% CI 1.23-6.54, P = 0.0405). Conclusions A substantial proportion of the study population exhibited subclinical and clinical cardiac dysfunction. SICFAIL provides reliable data on prevalence and determinants of SD, DD, and clinically overt HF in patients with acute IS according to current guidelines, enabling further clarification of its aetiological and prognostic role.},
  language  = {en}
}
@article{KraftDrechslerGunrebenetal.2014,
  author    = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph},
  title     = {Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study},
  series = {Cerebrovascular Diseases},
  volume    = {38},
  journal   = {Cerebrovascular Diseases},
  number    = {5},
  issn      = {1015-9770},
  doi       = {10.1159/000368434},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199076},
  pages     = {337-343},
  year      = {2014},
  abstract  = {Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58\%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26\% vs. 97 ± 24\%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk.},
  language  = {en}
}
@article{PhamHelluyKleinschnitzetal.2011,
  author    = {Pham, Mirko and Helluy, Xavier and Kleinschnitz, Christoph and Kraft, Peter and Bartsch, Andreas J. and Jakob, Peter and Nieswandt, Bernhard and Bendszus, Martin and Guido, Stoll},
  title     = {Sustained Reperfusion after Blockade of Glycoprotein-Receptor-Ib in Focal Cerebral Ischemia: An MRI Study at 17.6 Tesla},
  series = {PLoS ONE},
  volume    = {6},
  journal   = {PLoS ONE},
  number    = {4},
  doi       = {10.1371/journal.pone.0018386},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142608},
  pages     = {e18386},
  year      = {2011},
  abstract  = {Background: Inhibition of early platelet adhesion by blockade of glycoprotein-IB (GPIb) protects mice from ischemic stroke. To elucidate underlying mechanisms in-vivo, infarct development was followed by ultra-high field MRI at 17.6 Tesla. Methods: Cerebral infarction was induced by transient-middle-cerebral-artery-occlusion (tMCAO) for 1 hour in C57/BL6 control mice (N = 10) and mice treated with 100 mg Fab-fragments of the GPIb blocking antibody p0p/B 1 h after tMCAO (N = 10). To control for the effect of reperfusion, additional mice underwent permanent occlusion and received anti-GPIb treatment (N = 6; pMCAO) or remained without treatment (N = 3; pMCAO). MRI 2 h and 24 h after MCAO measured cerebral-blood-flow (CBF) by continuous arterial-spin labelling, the apparent-diffusion-coefficient (ADC), quantitative-T2 and T2-weighted imaging. All images were registered to a standard mouse brain MRI atlas and statistically analysed voxel-wise, and by cortico-subcortical ROI analysis. Results: Anti-GPIb treatment led to a relative increase of postischemic CBF vs. controls in the cortical territory of the MCA (2 h: 44.2 +/- 6.9 ml/100g/min versus 24 h: 60.5 +/- 8.4; p = 0.0012, F((1,18)) = 14.63) after tMCAO. Subcortical CBF 2 h after tMCAO was higher in anti-GPIb treated animals (45.3 +/- 5.9 vs. controls: 33.6 +/- 4.3; p = 0.04). In both regions, CBF findings were clearly related to a lower probability of infarction (Cortex/Subcortex of treated group: 35\%/65\% vs. controls: 95\%/100\%) and improved quantitative-T2 and ADC. After pMCAO, anti-GPIb treated mice developed similar infarcts preceded by severe irreversible hypoperfusion as controls after tMCAO indicating dependency of stroke protection on reperfusion. Conclusion: Blockade of platelet adhesion by anti-GPIb-Fab-fragments results in substantially improved CBF early during reperfusion. This finding was in exact spatial correspondence with the prevention of cerebral infarction and indicates in-vivo an increased patency of the microcirculation. Thus, progression of infarction during early ischemia and reperfusion can be mitigated by anti-platelet treatment.},
  language  = {en}
}
@article{SchuhmannKraftBieberetal.2019,
  author    = {Schuhmann, Michael K. and Kraft, Peter and Bieber, Michael and Kollikowski, Alexander M. and Schulze, Harald and Nieswandt, Bernhard and Pham, Mirko and Stegner, David and Stoll, Guido},
  title     = {Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice},
  series = {International Journal of Molecular Science},
  volume    = {20},
  journal   = {International Journal of Molecular Science},
  number    = {8},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20082019},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201700},
  year      = {2019},
  abstract  = {Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{-/-}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.},
  language  = {en}
}
@article{RuckBittnerAfzalietal.2015,
  author    = {Ruck, Tobias and Bittner, Stefan and Afzali, Ali Maisam and G{\"o}bel, Kerstin and Glumm, Sarah and Kraft, Peter and Sommer, Claudia and Kleinschnitz, Christoph and Preusse, Corinna and Stenzel, Werner and Wiendl, Heinz and Meuth, Sven G.},
  title     = {The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies},
  series = {Oncotarget},
  volume    = {6},
  journal   = {Oncotarget},
  number    = {41},
  doi       = {10.18632/oncotarget.6462},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136047},
  year      = {2015},
  abstract  = {NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naive CD8\(^+\) T cells into highly activated, cytotoxic \(CD8^+NKG2D^{high}\) T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. \(CD8^+NKG2D^{high}\) T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68\(^+\) macrophages as well as CD4\(^+\) T cells, and \(CD8^+NKG2D^+\) cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues.},
  language  = {en}
}
@article{KraftSchwarzMeijersetal.2010,
  author    = {Kraft, Peter and Schwarz, Tobias and Meijers, Joost C. M. and Stoll, Guido and Kleinschnitz, Christoph},
  title     = {Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68519},
  year      = {2010},
  abstract  = {Background: Thrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice. Methodology/Principal Findings: TAFI-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes weremeasured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H\&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p.0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO. Conclusion: Our study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge.},
  subject      = {Thrombus},
  language  = {en}
}
@article{BieberFoersterHaefelietal.2021,
  author    = {Bieber, Michael and Foerster, Kathrin I. and Haefeli, Walter E. and Pham, Mirko and Schuhmann, Michael K. and Kraft, Peter},
  title     = {Treatment with edoxaban attenuates acute stroke severity in mice by reducing blood-brain barrier damage and inflammation},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {18},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22189893},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284481},
  year      = {2021},
  abstract  = {Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood-brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.},
  language  = {en}
}
@article{GabrielJirůHillmannKraftetal.2020,
  author    = {Gabriel, Katharina M. A. and J{\´i}rů-Hillmann, Steffi and Kraft, Peter and Selig, Udo and R{\"u}cker, Victoria and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Keidel, Matthias and Soda, Hassan and Rascher, Alexandra and Schneider, Rolf and Pfau, Mathias and Hoffmann, Roy and Stenzel, Joachim and Benghebrid, Mohamed and Goebel, Tobias and Doerck, Sebastian and Kramer, Daniela and Haeusler, Karl Georg and Volkmann, Jens and Heuschmann, Peter U. and Fluri, Felix},
  title     = {Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke)},
  series = {BMC Neurology},
  volume    = {20},
  journal   = {BMC Neurology},
  doi       = {10.1186/s12883-020-01676-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229214},
  year      = {2020},
  abstract  = {Background Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. Methods The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. Results Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4\% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31\%), mainly in secondary stroke prevention; b) improvement over time (44\%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25\%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. Conclusion The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.},
  language  = {en}
}
@article{KraftDrechslerGunrebenetal.2014,
  author    = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Nieswandt, Bernhard and Stoll, Guido and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph},
  title     = {Von Willebrand Factor Regulation in Patients with Acute and Chronic Cerebrovascular Disease: A Pilot, Case-Control Study},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {6},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0099851},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119588},
  pages     = {e99851},
  year      = {2014},
  abstract  = {Background and Purpose In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods A case-control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. Results Patients with CCD (158±46\%) had significantly higher VWF levels than HV (113±36\%, P<0.001), but lower levels than AIS/TIA patients (200±95\%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05). Conclusions VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation.},
  language  = {en}
}