TY  - JOUR
AB  - Dietary factors have a significant impact on overall health and western diet (WD) disrupts arterial homeostasis, thereby promoting atherosclerosis. In our study, we investigated the effects of short-term WD on bone marrow vasculature and hematopoiesis in hypercholesterolemic mice. We found that WD rapidly remodels bone marrow arterioles, and these alterations persist even after WD cessation. The proximity between hematopoietic stem cells (HSCs) and arterioles increased with short-term WD, which was associated with a reduced HSC counts as well as an increased number of progenitor cells and a higher production of myeloid cells. Additionally, the remaining HSCs showed increased proliferation, potentially raising susceptibility to clonal hematopoiesis. Collectively, our findings show that short-term WD dramatically alters the bone marrow physiology with lasting consequences.
AU  - Bianchini, M.
AU  - Möller-Ramon, Z.*
AU  - Weber, C.*
AU  - Megens, R.T.A.*
AU  - Duchene, J.*
C1  - 68026
C2  - 54504
CY  - Rudigerstr 14, D-70469 Stuttgart, Germany
SP  - 1100-1104
TI  - Short-term western diet causes rapid and lasting alterations of bone marrow physiology.
JO  - Thromb. Haemost.
VL  - 123
IS  - 11
PB  - Georg Thieme Verlag Kg
PY  - 2023
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE:  Accurate and rapid assessment of coagulation status is necessary to guide thrombolysis or reversal of anticoagulation in stroke patients, but commercially available point-of-care (POC) assays are not suited for coagulation testing in patients treated with direct oral anticoagulants (DOACs). We aimed to evaluate the direct thrombin monitoring (DTM) test card by Helena Laboratories (Texas, United States) for anti-IIa-specific POC coagulation testing, hypothesizing that its POC-ecarin clotting time (POC-ECT) accurately reflects dabigatran plasma concentrations. METHODS:  A prospective single-center diagnostic study (ClinicalTrials.gov-identifier: NCT02825394) was conducted enrolling patients receiving a first dose of dabigatran and patients already on dabigatran treatment. Blood samples were collected before drug intake and 0.5, 1, 2, 8, and 12 hours after intake. POC-ECT was performed using whole blood (WB), citrated blood (CB), and citrated plasma (CP). Dabigatran plasma concentrations were determined by mass spectrometry. RESULTS:  In total, 240 blood samples from 40 patients contained 0 to 275 ng/mL of dabigatran. POC-ECT with WB/CB/CP ranged from 20 to 186/184/316 seconds. Pearson's correlation coefficient showed a strong correlation between dabigatran concentrations and POC-ECT with WB/CB/CP (R2  = 0.78/0.90/0.92). Dabigatran concentrations >30 and >50 ng/mL (thresholds for thrombolysis, surgery, and reversal therapy according to clinical guidelines) were detected by POC-ECT with WB/CB/CP (>36/35/45 and >43/45/59 seconds) with 95/97/97 and 96/98/97% sensitivity, and 81/87/94 and 74/60/91% specificity. CONCLUSION:  This first study evaluating DOAC-specific POC coagulation testing revealed an excellent correlation of POC-ECT with actual dabigatran concentrations. Detecting clinically relevant dabigatran levels with high sensitivity/specificity, the DTM assay represents a suitable diagnostic tool in acute stroke, hemorrhage, and urgent surgery.
AU  - Härtig, F.*
AU  - Birschmann, I.*
AU  - Peter, A.
AU  - Ebner, M.*
AU  - Spencer, C.*
AU  - Gramlich, M.*
AU  - Richter, H.*
AU  - Kuhn, J.*
AU  - Lehmann, R.
AU  - Blumenstock, G.*
AU  - Zuern, C.S.*
AU  - Ziemann, U.*
AU  - Poli, S.*
C1  - 61080
C2  - 50039
CY  - Rudigerstr 14, D-70469 Stuttgart, Germany
SP  - 782-791
TI  - Specific point-of-care testing of coagulation in patients treated with dabigatran.
JO  - Thromb. Haemost.
VL  - 121
IS  - 6
PB  - Georg Thieme Verlag Kg
PY  - 2021
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Metabolic complications in diabetic patients are driven by a combination of increased levels of nutrients and the presence of a proinflammatory environment. Methylglyoxal (MG) is a toxic byproduct of catabolism and has been strongly associated with the development of such complications. Macrophages are key mediators of inflammatory processes and their contribution to the development of metabolic complications has been demonstrated. However, a direct link between reactive metabolites and macrophage activation has not been demonstrated yet. Here, we show that acute MG treatment activated components of the p38 MAPK pathway and enhanced glycolysis in primary murine macrophages. MG induced a distinct gene expression profile sharing similarities with classically activated proinflammatory macrophages as well as metabolically activated macrophages usually found in obese patients. Transcriptomic analysis revealed a set of 15 surface markers specifically upregulated in MG-treated macrophages, thereby establishing a new set of targets for diagnostic or therapeutic purposes under high MG conditions, including diabetes. Overall, our study defines a new polarization state of macrophages that may specifically link aberrant macrophage activation to reactive metabolites in diabetes.
AU  - Tsokanos, F.-F.
AU  - Muley, C.
AU  - Khani, S.
AU  - Haß, D.
AU  - Fleming, T.
AU  - Wolff, G.
AU  - Bartelt, A.
AU  - Nawroth, P.P.*
AU  - Herzig, S.
C1  - 61983
C2  - 50423
CY  - Rudigerstr 14, D-70469 Stuttgart, Germany
SP  - 1464-1475
TI  - Methylglyoxal drives a distinct, nonclassical macrophage activation status.
JO  - Thromb. Haemost.
VL  - 121
IS  - 11
PB  - Georg Thieme Verlag Kg
PY  - 2021
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Endocannabinoids are a group of arachidonic acid-derived lipid mediators binding to cannabinoid receptors CB1 and CB2. An overactivity of the endocannabinoid system plays a pathophysiological role in the development of visceral obesity and insulin resistance. Moreover, elevated circulating endocannabinoid levels are also prevalent in atherosclerosis. The pathophysiological increase of endocannabinoid levels is due to an altered expression of endocannabinoid synthesizing and degrading enzymes induced by inflammatory mediators such as cytokines or lipids. Emerging experimental evidence suggests that enhanced endocannabinoid signalling affects atherosclerosis via multiple effects, including a modulation of vascular inflammation, leukocyte recruitment, macrophage cholesterol metabolism and consequently atherosclerotic plaque stability. In addition, recent findings in various metabolic disease models highlight the relevance of peripheral CB1 cannabinoid receptors in adipose tissue, liver and pancreas, which crucially regulate lipid and glucose metabolism as well as macrophage properties in these organs. This suggests that targeting the endocannabinoid system in the vasculature and peripheral organs might have a therapeutic potential for atherosclerosis by inhibiting vascular inflammation and improving metabolic risk factors. This review will provide a brief update on the effects of endocannabinoid signalling in atherosclerosis and related metabolic complications.
AU  - Guillamat-Prats, R.*
AU  - Rami, M.*
AU  - Herzig, S.
AU  - Steffens, S.*
C1  - 55755
C2  - 46562
CY  - Rudigerstr 14, D-70469 Stuttgart, Germany
SP  - 567-575
TI  - Endocannabinoid signalling in atherosclerosis and related metabolic complications.
JO  - Thromb. Haemost.
VL  - 119
IS  - 4
PB  - Georg Thieme Verlag Kg
PY  - 2019
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Background Direct oral anticoagulants (DOACs) are increasingly replacing vitamin K antagonists (VKA) for clinical indications requiring long-term oral anticoagulation. In contrast to VKA, treatment with DOAC including dabigatran-the only direct thrombin inhibitor amongst them-does not require therapeutic drug monitoring. However, in case of treatment complications (e.g., major haemorrhage) and conditions requiring urgent surgery or thrombolytic therapy, information about actual DOAC plasma levels is needed to guide treatment decisions. Due to short reagent stability, limited accuracy at low dabigatran levels and high heparin sensitivity, the applicability of the widely used Hemoclot thrombin inhibitor (HTI) coagulation assay is limited in the emergency setting. Methods Dabigatran concentrations of 288 citrated plasma samples taken from 48 dabigatran-treated patients with drug concentrations of up to 300 ng/mL were measured with the chromogenic anti-IIa Biophen direct thrombin inhibitor (BDTI) assay and results compared with HTI using ultra performance liquid chromatography-tandem mass spectrometry as the reference method for measuring dabigatran plasma concentrations. Results BDTI results showed a very strong correlation with dabigatran concentrations (r = 0.965, p < 0.0001) as well as a low intra-and inter-assay variation of <5%. Compared with HTI, BDTI provides an improved on-board reagent stability of 72 hours, rapid turnaround times comparable to routine coagulation assays, high accuracy at low drug levels and reduced heparin sensitivity. Conclusion The BDTI is an ideal coagulation assay for the around-the-clock determination of dabigatran plasma levels in clinical routine including emergency situations.
AU  - Poli, S.*
AU  - Härtig, F.*
AU  - Spencer, C.*
AU  - Ebner, M.*
AU  - Birschmann, I.*
AU  - Kuhn, J.*
AU  - Faix, S.*
AU  - Ziemann, U.*
AU  - Häring, H.-U.
AU  - Lehmann, R.
AU  - Peter, A.
AU  - Hörber, S.*
C1  - 52820
C2  - 44183
CY  - Stuttgart
SP  - 2369-2375
TI  - Diagnostic accuracy of a novel chromogenic direct thrombin inhibitor assay: Clinical experiences for dabigatran monitoring.
JO  - Thromb. Haemost.
VL  - 117
IS  - 12
PB  - Schattauer Gmbh-verlag Medizin Naturwissenschaften
PY  - 2017
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Cyclophilin A (CyPA) is involved in the pathophysiology of several inflammatory and cardiovascular diseases. To our knowledge, there is no specific inhibitor targeting extracellular CyPA without affecting other extracellular cyclophilins or intracellular CyPA functions. In this study, we developed an antibody-based inhibitor of extracellular CyPA and analysed its effects in vitro and in vivo. To generate a specific antibody, mice and rats were immunized with a peptide containing the extracellular matrix metalloproteinase inducer binding site and various antibody clones were selected and purified. At first, antibodies were tested for their binding capacity to recombinant CyPA and their functional activity. The clone 8H7-mAb was chosen for further experiments. 8H7-mAb reduced the CyPA-induced migration of inflammatory cells in vitro and in vivo. Furthermore, 8H7-mAb revealed strong antithrombotic effects by inhibiting CyPA-dependent activation of platelets and thrombus formation in vitro and in vivo. Surprisingly, 8H7-mAb did not influence in vivo tail bleeding time or in vitro whole blood coagulation parameters. Our study provides first evidence that antibody-based inhibition of extracellular CyPA inhibits thrombosis and thromboinflammation without affecting blood homeostasis. Thus, 8H7-mAb may be a promising compound for thrombi modulation in inflammatory diseases to prevent organ dysfunction.
AU  - von Ungern-Sternberg, S.N.I.*
AU  - Vogel, S.*
AU  - Walker-Allgaier, B.*
AU  - Geue, S.*
AU  - Maurer, A.*
AU  - Wild, A.*
AU  - Muenzer, P.*
AU  - Chatterjee, M.*
AU  - Heinzmann, D.*
AU  - Kremmer, E.
AU  - Borst, O.*
AU  - Loughran, P.*
AU  - Zernecke, A.*
AU  - Neal, M.D.*
AU  - Billiar, T.R.*
AU  - Gawaz, M.*
AU  - Seizer, P.*
C1  - 52486
C2  - 44012
CY  - Stuttgart
SP  - 2063-2078
TI  - Extracellular cyclophilin a augments platelet-dependent thrombosis and thromboinflammation.
JO  - Thromb. Haemost.
VL  - 117
IS  - 11
PB  - Schattauer Gmbh-verlag Medizin Naturwissenschaften
PY  - 2017
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood islet model and a syngeneic murine transplantation model. Indeed, Del-1 pretreatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.
AU  - Kourtzelis, I.*
AU  - Kotlabova, K.*
AU  - Lim, J.H.*
AU  - Mitroulis, I.*
AU  - Ferreira, A.*
AU  - Chen, L.*
AU  - Gercken, B.*
AU  - Steffen, A.
AU  - Kemter, E.*
AU  - Klotzsche-von Ameln, A.*
AU  - Waskow, C.*
AU  - Hosur, K.*
AU  - Chatzigeorgiou, A.*
AU  - Ludwig, B.
AU  - Wolf, E.*
AU  - Hajishengallis, G.*
AU  - Chavakis, T.*
C1  - 48531
C2  - 41171
CY  - Stuttgart
SP  - 781-788
TI  - Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation.
JO  - Thromb. Haemost.
VL  - 115
IS  - 4
PB  - Schattauer Gmbh-verlag Medizin Naturwissenschaften
PY  - 2016
SN  - 0340-6245
ER  - 

TY  - JOUR
AU  - von Hundelshausen, P.*
AU  - Oexle, K.
AU  - Bidzhekov, K.*
AU  - Schmitt, M.M.N.*
AU  - Hristov, M.*
AU  - Blanchet, X.*
AU  - Kaemmerer, H.*
AU  - Mátyás, G.*
AU  - Meitinger, T.
AU  - Weber, C.M.*
C1  - 44068
C2  - 36749
CY  - Stuttgart
SP  - 668-670
TI  - Recurrent spontaneous coronary dissections in a patient with a de novo fibrillin-1 mutation without Marfan syndrome.
JO  - Thromb. Haemost.
VL  - 113
IS  - 3
PB  - Schattauer Gmbh-verlag Medizin Naturwissenschaften
PY  - 2015
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Elevated fibrinogen levels are strongly and consistently associated with incident coronary heart disease (CHD). A possible causal contribution of fibrinogen in the pathway leading to atherothrombotic cardiovascular disease complications has been suggested. However, for implementation in clinical practice, data on validity and reliability, which are still scarce, are needed that are still scarce, especially in subjects with a history of CHD. For the present study, levels of plasma fibrinogen were measured in 200 post-myocardial infarction (post-MI) patients aged 39-76 years, with approximately six blood samples collected at monthly intervals between May 2003 and March 2004, giving a total of 1,144 samples. Inter-individual variability (between-subject variance component, VCb and coefficient of variation, CVb), intra-individual and analytical variability (VCw+a and CVw+a), intraclass correlation coefficient (ICC) and the number of measurements required for an ICC of 0.75 were estimated to assess the reliability of serial fibrinogen measurements. Mean fibrinogen concentration of all subjects over all samples was 3.34 g/l (standard deviation 0.67). Between-subject variation for fibrinogen was VCb = 0.34 (CVb,=17.5%) whereas within-subject and analytical variation was estimated as VCw+a = 0.14 (CVw+a=11.0%). The variation was mainly explained by between-subject variability, shown by the proportion of total variance of 71.3%. Two different measurements were required to reach sufficient reliability, if subjects with extreme values were not excluded. The present study indicates a fairly good reproducibility of serial individual fibrinogen measurements in post-MI subjects.
AU  - Baumert, J.J.
AU  - Karakas, M.*
AU  - Greven, S.*
AU  - Rückerl, R.
AU  - Peters, A.
AU  - Koenig, W.*
C1  - 7553
C2  - 29862
SP  - 895-902
TI  - Variability of fibrinogen measurements in post-myocardial infarction patients: Results from the AIRGENE study center Augsburg.
JO  - Thromb. Haemost.
VL  - 107
IS  - 5
PB  - Schattauer
PY  - 2012
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Platelets play a key role in the development of an acute coronary syndrome (ACS) and contribute to cardiovascular events. Platelet collagen receptor glycoprotein VI (GPVI) contributes significantly to platelet adhesion and thrombus formation in ACS. We consecutively investigated both the platelet count and the platelet surface expression of GPVI in 843 patients with a symptomatic coronary artery disease verified by coronary angiography. Four hundred fourteen patients presented with stable angina pectoris and 429 patients with ACS. Platelet surface expression of GPVI and CD62P was determined by flow cytometry and platelet count with a coulter counter, plasmatic soluble GPVI was measured by ELISA. Platelet GPVI expression in patients with ACS was compared to platelet count. Patients with ACS showed significantly elevated GPVI expression levels in the first and second quartiles of platelet count compared to patients with higher platelet count [mean fluorescence intensity (MFI) +/- standard deviation): 1(st) vs. 4(th): 20.44 +/- 6.1 vs. 18.62 +/- 3.7; p=0.012; 2(nd)vs.3(rd):21.2+/-8.5vs.18.76+/-3.7;P=0.03; 2(nd)vs.4(th): 21.2+/-8.5vs.18.62+/-3.7;P=0.004], which was paralleled in trend for the CD62P expression [MFI: 1(st) vs. 4(th): 11.2 +/- 6.8 vs. 12.3 +/- 9; p=0.057; 2(nd) vs. 3(rd): 16.3 +/- 16 vs.12.7 +/- 5.3; p=0.138; 2(nd) vs. 4(th): 16.3 +/- 16 vs.11 +/- 4.4; p=0.043]. In a subgroup of 48 patients with ACS, determination of soluble GPVI showed similar results [plasma GPVI (ng/ml): 1(st)vs.4(th): 1.6 +/- 0.6 vs. 1.2 +/- 0.4; p=0.046; 1(st) vs. 3(rd): 1.6 +/- 0.6 vs. 1.1 +/- 0.5; p=0.038; 2(nd) vs. 3(rd): 1.9 +/- 0.8 vs. 1.1 +/- 0.5; p=0.04; 2(nd) vs. 4(th): 1.9 +/- 0.8 vs. 1.2 +/- 0.4; p=0.056]. Thus, a lower platelet count comes along with a higher GPVI surface expression and plasma concentration in patients with ACS, which potentially reflects increased activation and enhanced recruitment of platelets to the site of vascular injury.
AU  - Bigalke, B.*
AU  - Stellos, K.*
AU  - Stakos, D.*
AU  - Joos, T.*
AU  - Pötz, O.*
AU  - Geisler, T.*
AU  - Bischofs, C.*
AU  - Kremmer, E.
AU  - Krämer, B.F.*
AU  - Seizer, P.*
AU  - May, A.E.*
AU  - Lindemann, S.*
AU  - Gawaz, M.*
C1  - 610
C2  - 26685
CY  - Stuttgart
SP  - 911-915
TI  - Influence of platelet count on the expression of platelet collagen receptor glycoprotein VI (GPVI) in patients with acute coronary syndrome.
JO  - Thromb. Haemost.
VL  - 101
IS  - 5
PB  - Schattauer
PY  - 2009
SN  - 0340-6245
ER  - 

TY  - JOUR
AB  - Previous studies reported a gender-specific association between plasma fibrinogen concentrations and incident hypertension. We systematically analysed polymorphisms and haplotypes across the fibrinogen gene cluster with fibrinogen levels and assessed their contribution to prevalent hypertension in 2,200 men and 2,159 women from the population-based MONICA/KORA Augsburg study. Eleven tagging single nucleotide polymorphisms (SNPs) were systematically selected in the three fibrinogen genes and haplotypes were reconstructed. The minor alleles of two SNPs, rs2227401 (FGB) and rs2070016 (FGA) and the haplotypes tagged by those variants, were significantly associated with higher fibrinogen concentrations in both, men and women, explaining 1% of the total variance of fibrinogen concentrations. In addition, a FGG haplotype, tagged by rs 1049636, was associated with lower concentrations of fibrinogen in women, but not in men. Regarding hypertension, we detected a significant association with a FGA promoter variant (rs2070008) in women only, whereas fibrinogen haplotypes were not associated with hypertension after correction for multiple comparisons in either men or women. In conclusion, our results suggest that variants in all three fibrinogen genes are significantly associated with differences in fibrinogen concentrations with modest contribution to phenotypic variance. It is likely that other genetic variants outside the fibrinogen gene loci are involved in the regulation of fibrinogen concentrations. In addition, one FGA promoter variant was significantly associated with hypertension in women. Confirmation of these findings by future studies is warranted.
AU  - Kolz, M.
AU  - Baumert, J.J.
AU  - Gohlke, H.
AU  - Grallert, H.
AU  - Döring, A.
AU  - Peters, A.
AU  - Wichmann, H.-E.
AU  - Koenig, W.*
AU  - Illig, T.
C1  - 1864
C2  - 26104
SP  - 317-324
TI  - Association study between variants in the fibrinogen gene cluster, fibrinogen levels and hypertension: Results from the MONICA/KORA study.
JO  - Thromb. Haemost.
VL  - 101
IS  - 2
PB  - Schattauer
PY  - 2009
SN  - 0340-6245
ER  - 

TY  - JOUR
AU  - Bültmann, A.*
AU  - Herdeg, C.*
AU  - Li, Z.*
AU  - Münch, G.*
AU  - Baumgartner, C.*
AU  - Langer, H.*
AU  - Kremmer, E.
AU  - Geisler, T.*
AU  - May, A.*
AU  - Ungerer, M.*
AU  - Gawaz, M.*
C1  - 4934
C2  - 23895
SP  - 763-766
TI  - Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus foramation in vivo.
JO  - Thromb. Haemost.
VL  - 95
PY  - 2006
SN  - 0340-6245
ER  - 

TY  - JOUR
AU  - Thorand, B.
AU  - Baumert, J.J.
AU  - Döring, A.
AU  - Schneider, A.E.
AU  - Chambless, L.*
AU  - Löwel, H.
AU  - Kolb, H.*
AU  - König, W.*
C1  - 3484
C2  - 23847
SP  - 134-141
TI  - Association of cardiovascular risk factors with markers of endothelial dysfunction in middle-aged men and woman: Results from the MONICA/KORA Augsburg study.
JO  - Thromb. Haemost.
VL  - 95
PY  - 2006
SN  - 0340-6245
ER  - 

TY  - JOUR
AU  - Klopp, N.
AU  - Oldenburg, J.*
AU  - Uen, C.
AU  - Schneppenheim, R.*
AU  - Graw, J.
C1  - 9849
C2  - 20262
SP  - 357-360
TI  - 11 Hemophilia A Patients without Mutations in the Factor VIII Encoding Gene.
JO  - Thromb. Haemost.
VL  - 88
PB  - Schattauer
PY  - 2002
SN  - 0340-6245
ER  - 

TY  - JOUR
AU  - Alban, S.*
AU  - Gastpar, R.
C1  - 21708
C2  - 19901
SP  - 824-829
TI  - Plasma Levels of Total and Free Tissue Factor Pathway Inhibitor (TFPI) as Individual Pharmacological Parameters of Various Heparins.
JO  - Thromb. Haemost.
VL  - 85
PY  - 2001
SN  - 0340-6245
ER  -