TY  - JOUR
AB  - BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. OBJECTIVES: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.
AU  - Gallego-Fabrega, C.*
AU  - Temprano-Sagrera, G.*
AU  - Cárcel-Márquez, J.*
AU  - Muiño, E.*
AU  - Cullell, N.*
AU  - Lledós, M.*
AU  - Llucià-Carol, L.*
AU  - Martin-Campos, J.M.*
AU  - Sobrino, T.*
AU  - Castillo, J.*
AU  - Millán, M.*
AU  - Muñoz-Narbona, L.*
AU  - López-Cancio, E.*
AU  - Ribó, M.*
AU  - Alvarez-Sabin, J.*
AU  - Jiménez-Conde, J.*
AU  - Roquer, J.*
AU  - Tur, S.*
AU  - Obach, V.*
AU  - Arenillas, J.F.*
AU  - Segura, T.*
AU  - Serrano-Heras, G.*
AU  - Martí-Fàbregas, J.*
AU  - Freijo-Guerrero, M.*
AU  - Moniche, F.*
AU  - Castellanos, M.D.M.*
AU  - Morrison, A.C.*
AU  - Smith, N.L.*
AU  - de Vries, P.S.*
AU  - Fernandez-Cadenas, I.*
AU  - Sabater-Lleal, M.*
AU  - Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (Peters, A.)
AU  - Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (Müller-Nurasyid, M.)
C1  - 71358
C2  - 56053
SP  - 936-950
TI  - A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment.
JO  - J. Thromb. Haemost.
VL  - 22
IS  - 4
PY  - 2024
SN  - 1538-7933
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases. METHODS: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients. RESULTS: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment. CONCLUSIONS: Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.
AU  - Polzin, A.*
AU  - Benkhoff, M.*
AU  - Thienel, M.*
AU  - Barcik, M.*
AU  - Mourikis, P.*
AU  - Shchurovska, K.*
AU  - Helten, C.*
AU  - Ehreiser, V.*
AU  - Zhe, Z.*
AU  - von Wulffen, F.*
AU  - Theiss, A.*
AU  - Peri, S.*
AU  - Cremer, S.*
AU  - Ahlbrecht, S.*
AU  - Zako, S.*
AU  - Wildeis, L.*
AU  - Al-Kassis, G.*
AU  - Metzen, D.*
AU  - Utz, A.*
AU  - Hu, H.*
AU  - Vornholz, L.*
AU  - Pavic, G.*
AU  - Lüsebrink, E.*
AU  - Strecker, J.*
AU  - Tiedt, S.*
AU  - Cramer, M.J.*
AU  - Gliem, M.*
AU  - Ruck, T.*
AU  - Meuth, S.G.*
AU  - Zeus, T.*
AU  - Mayr, C.
AU  - Schiller, H. B.
AU  - Simon, L.*
AU  - Massberg, S.*
AU  - Kelm, M.*
AU  - Petzold, T.*
C1  - 72394
C2  - 56567
TI  - Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration.
JO  - J. Thromb. Haemost.
PY  - 2024
SN  - 1538-7933
ER  - 

TY  - JOUR
AU  - Karakas, M.*
AU  - Baumert, J.J.
AU  - Herder, C.*
AU  - Rottbauer, W.*
AU  - Meisinger, C.
AU  - Koenig, W.*
AU  - Thorand, B.
C1  - 6319
C2  - 28501
CY  - Malden, USA
SP  - 1078-1080
TI  - Soluble thrombomodulin in coronary heart disease: Lack of an association in the MONICA/KORA case-cohort study.
JO  - J. Thromb. Haemost.
VL  - 9
IS  - 5
PB  - Wiley-Blackwell
PY  - 2011
SN  - 1538-7933
ER  - 

TY  - JOUR
AB  - BACKGROUND: Platelets play a central role in hemostasis, in inflammatory diseases such as atherosclerosis, and during thrombus formation following vascular injury. Thereby, platelets interact intensively with monocytes and enhance their recruitment to the vascular wall. OBJECTIVES: To investigate the role of the extracellular matrix metalloproteinase inducer (EMMPRIN) in platelet-monocyte interactions METHODS AND RESULTS: Isolated human monocytes were perfused in vitro over firmly adherent platelets to allow investigation of the role of EMMPRIN in platelet-monocyte interactions under flow conditions. Monocytes readily bound to surface-adherent platelets. Both antibody blockade and gene silencing of monocyte EMMPRIN substantially attenuated firm adhesion of monocytes to platelets at arterial and venous shear rates. In vivo, platelet interactions with the murine monocyte cell line ANA-1 were significantly decreased when ANA-1 cells were pretreated with EMMPRIN-silencing small interfering RNA prior to injection into wild-type mice. Using intravital microscopy, we showed that recruitment of EMMPRIN-silenced ANA-1 to the injured carotid artery was significantly reduced as compared with control cells. Further silencing of EMMPRIN resulted in significantly fewer ANA-1-platelet aggregates in the mouse circulation as determined by flow cytometry. Finally, we identified glycoprotein (GP)VI as a critical corresponding receptor on platelets that mediates interaction with monocyte EMMPRIN. Thus, blocking of GPVI inhibited the effect of EMMPRIN on firm monocyte adhesion to platelets under arterial flow conditions in vitro, and abrogated EMMPRIN-mediated platelet-monocyte aggregate formation in vivo. CONCLUSIONS: EMMPRIN supports platelet-monocyte interactions and promotes monocyte recruitment to the arterial wall. Therefore, EMMPRIN might represent a novel target to reduce vascular inflammation and atherosclerotic lesion development.
AU  - Schulz, C.*
AU  - von Brühl, M.L.*
AU  - Barocke, V.*
AU  - Cullen, P.*
AU  - Mayer, K.*
AU  - Okrojek, R.*
AU  - Steinhart, A.*
AU  - Ahmad, Z.*
AU  - Kremmer, E.
AU  - Nieswandt, B.*
AU  - Frampton, J.*
AU  - Massberg, S.*
AU  - Schmidt, R.*
C1  - 6060
C2  - 29118
SP  - 1007-1019
TI  - EMMPRIN (CD147/basigin) mediates platelet-monocyte interactions in vivo and augments monocyte recruitment to the vascular wall.
JO  - J. Thromb. Haemost.
VL  - 9
IS  - 5
PB  - International Society on Thrombosis and Haemostasis
PY  - 2011
SN  - 1538-7933
ER  - 

TY  - JOUR
AB  - SUMMARY BACKGROUND: The translocation of nanoparticles in the lung toward effector organs via the circulation is considered an important direct pathway for systemic effects of nanoparticles after inhalation. Recently, we have reported that a moderate dose of systemically administered nanosized carbon black particles exerted thrombogenic effects in hepatic microvessels of healthy mice. OBJECTIVES: This study addresses the questions of whether similar thrombogenic effects are also evoked upon inhalation of nanosized carbon particles (NCP) and whether NCP-induced hepatic platelet accumulation is associated with pulmonary or systemic inflammation. METHODS: Two and 8 h after a 24-h exposure to either filtered air or to NCP, intravital fluorescence microscopy of the hepatic microcirculation was performed in C57Bl/6 mice. Parameters of pulmonary or systemic inflammatory response were determined in bronchoalveolar lavage and blood/plasma samples. RESULTS: Inhalative exposure to NCP caused platelet accumulation in the hepatic microvasculature, whereas leukocyte recruitment and sinusoidal perfusion did not differ from controls. Fibrinogen deposition was detected by immunohistochemistry in both hepatic and cardiac microvessels from NCP-exposed mice. In contrast, inhalation of NCP affected neither the plasma levels of proinflammatory cytokines nor blood cell counts. Moreover, the bronchoalveolar lavage data indicate that no significant inflammatory response occurred in the lung. CONCLUSIONS: Thus, exposure to NCP exerts thrombogenic effects in the microcirculation of healthy mice independent of the route of administration (i.e. inhalation or systemic intra-arterial administration). The NCP-induced thrombogenic effects are not liver specific, are associated with neither a local nor a systemic inflammatory response, and seem to be independent of pulmonary inflammation.
AU  - Khandoga, A.*
AU  - Stöger, T.
AU  - Khandoga, A.G.*
AU  - Bihari, P.*
AU  - Karg, E.W.
AU  - Ettehadieh, D.
AU  - Lakatos, S.*
AU  - Fent, J.*
AU  - Schulz, S.
AU  - Krombach, F.*
C1  - 5178
C2  - 27609
SP  - 1632-1640
TI  - Platelet adhesion and fibrinogen deposition in murine microvessels upon inhalation of nanosized carbon particles.
JO  - J. Thromb. Haemost.
VL  - 8
IS  - 7
PB  - Wiley-Blackwell Publishing
PY  - 2010
SN  - 1538-7933
ER  - 

TY  - JOUR
AU  - El-Maarri, O.*
AU  - Herbiniaux, U.*
AU  - Graw, J.
AU  - Schröder, J.*
AU  - Terzic, A.
AU  - Watzka, M.*
AU  - Brackmann, H.H.*
AU  - Schramm, W.*
AU  - Hanfland, P.*
AU  - Schwaab, R.*
AU  - Müller, C.R.*
C1  - 3674
C2  - 23237
SP  - 332-339
TI  - Analysis of mRNA in hemophilia A patients with undetectable mutations reveals normal splicing in the factor VIII gene.
JO  - J. Thromb. Haemost.
VL  - 3
PY  - 2005
SN  - 1538-7933
ER  -