T Renné

Publications of T Renné

• Platelet- and erythrocyte-derived microparticles trigger thrombin generation via Factor XIIa.

  Authors: P E J van der Meijden, M van Schilfgaarde, R van Oerle, T Renné, H Ten Cate, H M H Spronk

  Journal of thrombosis and haemostasis : JTH. 04/2012;

  Background: Procoagulant properties of microparticles (MPs) are due to the presence of phosphatidylserine (PS) and tissue factor on their surface. The latter has been demonstrated especially on MPsBackground: Procoagulant properties of microparticles (MPs) are due to the presence of phosphatidylserine (PS) and tissue factor on their surface. The latter has been demonstrated especially on MPs derived from monocytes. Objectives: To investigate the relative contribution of tissue factor and Factor XII for initiating coagulation on MPs derived from monocytes, platelets and erythrocytes. Methods: MPs were isolated from calcium ionophore-stimulated platelets, erythrocytes and monocytic THP-1 cells. MPs were quantified, characterized for cell-specific antigens and analyzed for tissue factor, PS exposure and their thrombin generating potential. Results: MP number was not proportional to PS exposure and the majority of the MPs exposed PS. Tissue factor activity was undetectable on platelet- and erythrocyte-derived MPs (< 1 fM/nM PS), whereas monocyte-derived MPs exposed tissue factor (32 fM/nM PS). Platelet-, erythrocyte- and monocyte-derived MPs, but not purified phospholipids, initiated thrombin generation in normal plasma in the absence of an external trigger (lag time < 11 min). Deficiency or inhibition of Factor VII, had no effect on thrombin generation induced by platelet- and erythrocyte-derived MPs, but interfered with monocyte MP-triggered coagulation. Platelet- and erythrocyte-derived MPs completely failed to induce thrombin generation in Factor XII-deficient plasma. In contrast, monocyte-derived MPs induced similar thrombin generation in normal versus Factor XII-deficient plasma. Conclusion: MPs from platelets and erythrocytes not only propagate coagulation by exposing PS but also initiate thrombin generation independently of tissue factor in a Factor XII-dependent manner. In contrast, monocyte-derived MPs trigger coagulation predominantly via tissue factor. © 2012 International Society on Thrombosis and Haemostasis.

• Factor XII activation is essential to sustain the procoagulant effects of particulate matter.

  Authors: E Kilinç, R Van Oerle, J I Borissoff, C Oschatz, M E Gerlofs-Nijland, N A Janssen, F R Cassee, T Sandström, T Renné, H Ten Cate, H M H Spronk

  Journal of thrombosis and haemostasis : JTH. 04/2011; 9(7):1359-67.

  Particulate matter (PM) is a key component of ambient air pollution and has been associated with an increased risk of thrombotic events and mortality. The underlying mechanisms remain unclear.  ToParticulate matter (PM) is a key component of ambient air pollution and has been associated with an increased risk of thrombotic events and mortality. The underlying mechanisms remain unclear.  To study the mechanisms of PM-driven procoagulant activity in human plasma and to investigate mainly, the coagulation driven by ultrafine particles (UFPs; < 0.1 μm) in genetically modified mice. Thrombin generation in response to PM of different sizes was assessed in normal human platelet-poor plasma, as well as in plasmas deficient in the intrinsic pathway proteases factors XII (FXII) or XI (FXI). In addition, UFPs were intratracheally instilled in wild-type (WT) and FXII-deficient (FXII(-/-) ) mice and plasma thrombin generation was analyzed in plasma from treated mice at 4 and 20 h post-exposure. In normal human plasma, thrombin generation was enhanced in the presence of PM, whereas PM-driven thrombin formation was completely abolished in FXII- and FXI-deficient plasma. UFPs induced a transient increase in tissue factor (TF)-driven thrombin formation at 4 h post-instillation in WT mice compared with saline instillation. Intratracheal instillation of UFPs resulted in a procoagulant response in WT mice plasma at 20 h, whereas it was entirely suppressed in FXII(-/-) mice.  Overall, the data suggest that PM promotes its early procoagulant actions mostly through the TF-driven extrinsic pathway of coagulation, whereas PM-driven long lasting thrombogenic effects are predominantly mediated via formation of activated FXII. Hence, FXII-driven thrombin formation may be relevant to an enhanced thrombotic susceptibility upon chronic exposure to PM in humans.

• Decreased active von Willebrand factor level owing to shear stress in aortic stenosis patients.

  Authors: M J Hollestelle, C M Loots, A Squizzato, T Renné, B J Bouma, P G de Groot, P J Lenting, J C M Meijers, V E A Gerdes

  Journal of thrombosis and haemostasis : JTH. 02/2011; 9(5):953-8.

  Aortic stenosis patients often show bleeding complications. Previously, a prolonged platelet function analyzer (PFA-100) closure time was observed with plasma of severe aortic stenosis patients. ToAortic stenosis patients often show bleeding complications. Previously, a prolonged platelet function analyzer (PFA-100) closure time was observed with plasma of severe aortic stenosis patients. To elucidate a possible role of circulating preactivated von Willebrand factor (VWF), we determined the level of VWF in its active, platelet-binding conformation in plasma of patients with aortic stenosis. Sixty-two aortic stenosis patients were included in this study. VWF and related parameters were measured, and the results were related to severity of aortic stenosis. VWF activation factor, indicating the proportion of circulating VWF able to bind to platelets, correlated negatively with peak transvalvular gradient and PFA-100 closure time. No correlation was observed between ADAMTS13 activity and peak transvalvular gradient or PFA-100 closure time. Both VWF antigen and VWF propeptide levels were significantly higher in patients with mild and moderate aortic stenosis, but not in those with severe stenosis. Our data demonstrate that the aortic pressure gradient is inversely associated with VWF activation factor, but not with VWF antigen or VWF multimerization in patients with aortic stenosis. These findings might have implications for the bleeding observed in patients with aortic stenosis.

• Enhanced cortical reperfusion protects coagulation factor XII-deficient mice from ischemic stroke as revealed by high-field MRI.

  Authors: M Pham, C Kleinschnitz, X Helluy, A J Bartsch, M Austinat, V C Behr, T Renné, B Nieswandt, G Stoll, M Bendszus

  NeuroImage. 12/2009;

  Intrinsic coagulation factor XII deficient (FXII(-/-)) mice are protected from ischemic stroke. To elucidate underlying mechanisms we investigated the early ischemic period in vivo by multimodalIntrinsic coagulation factor XII deficient (FXII(-/-)) mice are protected from ischemic stroke. To elucidate underlying mechanisms we investigated the early ischemic period in vivo by multimodal magnetic resonance imaging (MRI) at 17.6 Tesla. Cerebral ischemia was induced by either transient (60 min) or permanent occlusion of the middle cerebral artery (t/pMCAO). 10 FXII(-/-) mice underwent t- , 10 FXII(-/-) mice p- and 10 Wildtype (Wt) mice tMCAO. Cerebral blood flow (CBF), diffusion-weighted-imaging (DWI) and T2-relaxometry were measured at 2 h and 24 h after MCAO. Outcome measures were evaluated after motion correction and normalization to atlas space. 2 h after tMCAO CBF reduction was similar in FXII(-/-) and Wt mice extending over cortical (CBF (ml/100 g/min) 33.6+/-6.9 vs. 35.3+/-4.6, p=0.42) and subcortical regions (25.7+/-4.5 vs. 31.6+/-4.0, p=0.17). At 24 h, recovery of cortical CBF by +36% was observed only in tMCAO FXII(-/-) mice contrasting a further decrease of -48% in Wt mice after tMCAO (p=0.02, F((1,18))=6.24). In FXII(-/-) mice in which patency of the MCA was not restored (pMCAO) a further decrease of -75% was observed. Cortical reperfusion in tMCAO FXII(-/-) mice was related to a lower risk of infarction of 59% vs. 93% in Wt mice (p=0.04). Subcortical CBF was similarly decreased in both tMCAO groups (Wt and FXII(-/-)) relating to a similar risk of infarction of 89% (Wt) vs. 99% (FXII(-/-), p=0.17). Deficiency of FXII allows neocortical reperfusion after tMCAO and rescues brain tissue by this mechanism. This study supports the concept of FXII as a promising new target for stroke prevention and therapy.

• Factor XI deficiency in animal models.

  Authors: T Renné, C Oschatz, S Seifert, F Müller, J Antovic, M Karlman, P M Benz

  Journal of thrombosis and haemostasis : JTH. 08/2009; 7 Suppl 1:79-83.

  The blood coagulation system forms fibrin to limit blood loss from sites of injury, but also contributes to occlusive diseases such as deep vein thrombosis, myocardial infarction, and stroke. In theThe blood coagulation system forms fibrin to limit blood loss from sites of injury, but also contributes to occlusive diseases such as deep vein thrombosis, myocardial infarction, and stroke. In the current model of a coagulation balance, normal hemostasis and thrombosis represent two sides of the same coin; however, data from coagulation factor XI-deficient animal models have challenged this dogma. Gene targeting of factor XI, a serine protease of the intrinsic pathway of coagulation, severely impairs arterial thrombus formation but is not associated with excessive bleeding. Mechanistically, factor XI may be activated by factor XII following contact activation or by thrombin in a feedback activation loop. This review focuses on the role of factor XI, and its deficiency states as novel target for prevention of thrombosis with low bleeding risk in animal models.

• Inhibition of platelets by insulin? A reply to a rebuttal letter.

  Authors: S Gambaryan, J Geiger, T Renné, U Walter

  Journal of thrombosis and haemostasis : JTH. 01/2009;

• Improvement of vascular function by acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes mellitus.

  Authors: A Schäfer, D Fraccarollo, S Pförtsch, U Flierl, C Vogt, J Pfrang, A Kobsar, T Renné, M Eigenthaler, G Ertl, J Bauersachs

  British journal of pharmacology. 04/2008; 153(5):886-93.

  BACKGROUND AND PURPOSE: Diabetes-associated vascular dysfunction contributes to increased cardiovascular risk. We investigated whether the phosphodiesterase-5 inhibitor sildenafil would improveBACKGROUND AND PURPOSE: Diabetes-associated vascular dysfunction contributes to increased cardiovascular risk. We investigated whether the phosphodiesterase-5 inhibitor sildenafil would improve vascular function in diabetic rats. EXPERIMENTAL APPROACH: Male Wistar rats were injected with streptozotocin (50 mg kg(-1), i.v.) to induce insulin-deficient diabetes. Direct effects of sildenafil as well as modification of endothelium-dependent and -independent vasorelaxation were investigated in vitro. The effects of acute and chronic (2 week) treatment in vivo of sildenafil on vascular function were also characterized in isolated aortic segments in organ bath chambers 4 weeks after diabetes induction. KEY RESULTS: Sildenafil induced a concentration-dependent vasorelaxation, which was attenuated by the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine. Acetylcholine-induced endothelium-dependent as well as endothelium-independent relaxation induced by the NO donor, DEA-NONOate, was significantly reduced in aortae from diabetic rats. Incubation with sildenafil in vitro normalized both endothelium-dependent and -independent relaxation in aortae from diabetic rats. Acute as well as chronic in vivo treatment with sildenafil resulted in enhanced endothelium-dependent and -independent vasorelaxation. Superoxide formation was increased in diabetes, associated with enhanced membrane expression of the NAD(P)H oxidase subunit gp91(phox) and Rac, which were both reduced by chronic treatment with sildenafil. CONCLUSIONS AND IMPLICATIONS: We demonstrate that sildenafil treatment rapidly and chronically improves vascular relaxation in diabetic rats. Treatment with sildenafil might provide a similarly beneficial effect in diabetic patients.

• The intrinsic pathway of coagulation: a target for treating thromboembolic disease?

  Authors: D Gailani, T Renné

  Journal of thrombosis and haemostasis : JTH. 07/2007; 5(6):1106-12.

  The classic intrinsic pathway of coagulation is triggered by contact activation of the plasma protease factor (F)XII, followed by sequential proteolytic activation of FX1 and FIX. While a keyThe classic intrinsic pathway of coagulation is triggered by contact activation of the plasma protease factor (F)XII, followed by sequential proteolytic activation of FX1 and FIX. While a key mechanism for initiating coagulation in some clinically useful in vitro assays, the absence of abnormal bleeding associated with congenital FXII deficiency indicates that the intrinsic pathway is not important for normal blood coagulation in vivo. However, recent work with mice lacking FXII or FXI suggest that these proteases make important contributions to formation of pathologic intravascular thrombi. In models of arterial injury, FXII or FXI null mice are protected from formation of platelet rich occlusive thrombi to a degree similar to that seen in FIX deficient mice (a model for the severe bleeding disorder hemophilia B) or to wild type mice treated with high dose heparin. FXII or FXI deficiency does not appear to prevent the initiation of thrombus formation in these models, but instead causes significant thrombus instability that prevents occlusion of the vessel. These findings raise the possibility that a pathway similar or identical to the intrinsic pathway may operate in vivo under some circumstances. Furthermore, the disproportionate importance of FXII and FXI to occlusive thrombus formation compared to normal hemostasis makes these proteases attractive candidates for therapeutic inhibitors to treat or prevent thromboembolic disorders.

• Enhanced cortical reperfusion protects coagulation factor XII-deficient mice from ischemic stroke as revealed by high-field MRI

  Authors: M. Pham, C. Kleinschnitz, X. Helluy, A.J. Bartsch, M. Austinat, V.C. Behr, T. Renné, B. Nieswandt, G. Stoll, M. Bendszus

  NeuroImage.

  Intrinsic coagulation factor XII deficient (FXII−/−) mice are protected from ischemic stroke. To elucidate underlying mechanisms we investigated the early ischemic period in vivo by multimodalIntrinsic coagulation factor XII deficient (FXII−/−) mice are protected from ischemic stroke. To elucidate underlying mechanisms we investigated the early ischemic period in vivo by multimodal magnetic resonance imaging (MRI) at 17.6 Tesla.Cerebral ischemia was induced by either transient (60 min) or permanent occlusion of the middle cerebral artery (t/pMCAO). 10 FXII−/− mice underwent t- , 10 FXII−/− mice p- and 10 Wildtype (Wt) mice tMCAO. Cerebral blood flow (CBF), diffusion-weighted-imaging (DWI) and T2-relaxometry were measured at 2 h and 24 h after MCAO. Outcome measures were evaluated after motion correction and normalization to atlas space. 2 h after tMCAO CBF reduction was similar in FXII−/− and Wt mice extending over cortical (CBF (ml/100 g/min) 33.6 ± 6.9 vs. 35.3 ± 4.6, p = 0.42) and subcortical regions (25.7 ± 4.5 vs. 31.6 ± 4.0, p = 0.17). At 24 h, recovery of cortical CBF by +36% was observed only in tMCAO FXII−/− mice contrasting a further decrease of – 30% in Wt mice after tMCAO (p = 0.02, F(1,18) = 6.24). In FXII−/− mice in which patency of the MCA was not restored (pMCAO) a further decrease of − 75% was observed. Cortical reperfusion in tMCAO FXII−/− mice was related to a lower risk of infarction of 59% vs. 93% in Wt mice (p = 0.04). Subcortical CBF was similarly decreased in both tMCAO groups (Wt and FXII−/−) relating to a similar risk of infarction of 89% (Wt) vs. 99% (FXII−/−, p = 0.17).Deficiency of FXII allows neocortical reperfusion after tMCAO and rescues brain tissue by this mechanism. This study supports the concept of FXII as a promising new target for stroke prevention and therapy.