Oliver Grottke

University of Toronto, Toronto, Ontario, Canada

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Publications (68)184.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Clinical use of non-vitamin K antagonist oral anticoagulants is increasingly well established. However, specific agents for reversal of these drugs are not currently available. It was to objective of this study to investigate the impact of activated prothrombin complex concentrate (aPCC) on the anticoagulant effects of dabigatran in a randomised, controlled, porcine trauma model. Twenty-one pigs received oral and intravenous dabigatran, resulting in supratherapeutic plasma concentrations. Twelve minutes after injury (standardised bilateral femur fractures and blunt liver injury), animals (n=7/group) received 25 or 50 U/kg aPCC (aPCC25 and aPCC50) or placebo (control) and were followed for 5 hours. The primary endpoint was total volume of blood loss (BL). Haemodynamic and coagulation variables (prothrombin time [PT], activated partial thromboplastin time, diluted thrombin time, thrombin-antithrombin complexes, thromboelastometry, thrombin generation and D-dimers) were measured. Twelve minutes post-injury, BL was similar between groups. Compared with control (total BL: 3807 ± 570 ml) and aPCC25 (3690 ± 454 ml; p=0.77 vs control), a significant reduction in total BL (1639 ± 276 ml; p< 0.0001) and improved survival (p< 0.05) was observed with aPCC50. Dabigatran's anticoagulant effects were effectively treated in the aPCC50 group, as measured by several parameters including EXTEM clotting time (CT) and PT. In contrast, with aPCC25, laboratory values were initially corrected but subsequently deteriorated due to ongoing blood loss. Thromboembolic or bleeding effects were not detected. In conclusion, blood loss following trauma in dabigatran-anticoagulated pigs was successfully reduced by 50 U/kg aPCC. Optimal methodology for measuring amelioration of dabigatran anticoagulation by aPCC is yet to be determined.
    Thrombosis and Haemostasis 09/2015; 115(1). DOI:10.1160/TH15-03-0266 · 4.98 Impact Factor
  • Anesthesiology 09/2015; DOI:10.1097/ALN.0000000000000863 · 5.88 Impact Factor
  • O Grottke
    Der Anaesthesist 07/2015; DOI:10.1007/s00101-015-0059-x · 0.76 Impact Factor
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    ABSTRACT: Recombinant factor VIIa (rFVIIa) is registered for use in haemophilia with inhibitors and other rare bleeding disorders, but has also been used in various other clinical conditions to terminate life-threatening bleeding. Underlying conditions (e.g. coagulopathy) and dosing may affect treatment efficacy. The objective of the present study was to evaluate the impact of increasing doses of rFVIIa on blood loss and coagulation assays in haemodiluted and hypothermic pigs undergoing blunt liver injury. A grade III blunt liver injury was induced in 28 pigs after 70% haemodilution and cooling to 32.6-33.4°C. Ten minutes after trauma, animals randomly received placebo or 90, 180 or 360 μg/kg rFVIIa. Global coagulation parameters, thromboelastometry (TEM) and plasma thrombin generation (TG) were determined at different time points during the observation period of 120 minutes. Total blood loss was significantly lower following 90 μg/kg rFVIIa (1206 [1138-1470] mL) relative to placebo (2677 [2337-3068] mL; p<0.05), with no increased effect with higher dose levels of rFVIIa. Following trauma and haemodilution, coagulation was impaired relative to baseline in both TEM and TG analysis. At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group. Similarly, rFVIIa improved coagulation kinetics in TG. As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG. Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events. Early administration of 90 μg/kg rFVIIa reduced blood loss in pigs undergoing blunt liver injury even after severe haemodilution and hypothermia, with no further effect of higher dose levels. Coagulation assays showed impaired coagulation in coagulopathic animals, with a dose-independent improvement in animals treated with rFVIIa.
    PLoS ONE 06/2015; 10(6):e0113979. DOI:10.1371/journal.pone.0113979 · 3.23 Impact Factor
  • Oliver Grottke · Hugo ten Cate
    Pediatric Anesthesia 06/2015; 25(6). DOI:10.1111/pan.12650 · 1.85 Impact Factor
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    ABSTRACT: Introduction: In a 24-hour porcine model of liver injury, we showed that fibrinogen supplementation does not downregulate endogenous fibrinogen synthesis. Here we report data from the same study showing the impact of fibrinogen on coagulation variables.
    Clinical and Applied Thrombosis/Hemostasis 05/2015; DOI:10.1177/1076029615584662 · 2.39 Impact Factor
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    ABSTRACT: In vitro test systems for ECMO (mock loop) represent an interesting alternative to complex and expensive in-vivo test systems to analyze the pathomechanisms leading to insufficient biocompatibility. Data on mock loop systems are limited, and operation times are constricted to a maximum duration of six hours. This study aims at a 12 hours operation time and frequent monitoring of markers for insufficient biocompatibility in two experimental settings. Porcine blood circulated in a mock loop without any modifications, or the circuit was operated with a CO2 enhanced gas (5 % CO2/21 % O2/74 % N2) in combination with a nutrient solution (PAGGSM). Coagulation parameters changed over time without differences between the two groups. In the unmodified test setting, a pH-increase was detected after one hour, followed by significantly increased levels of free hemoglobin as a marker for hemolysis and elevated numbers of activated platelets, which correlate with detected von Willebrand factor, microparticles, and IL-[beta]. Pro-inflammatory cytokine levels were significantly increased after 12 hours. In contrast, these parameters remained constant in the modified test setting providing proof of a stable operating in-vitro mock loop system with an extended/prolonged operation time.
    ASAIO Journal 05/2015; Publish Ahead of Print(5):1. DOI:10.1097/MAT.0000000000000252 · 1.52 Impact Factor
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    ABSTRACT: In emergency medicine, the benefits of high-fidelity simulation (SIM) are widely accepted and standardized patients (SP) are known to mimic real patients accurately. However, only limited data are available concerning physicians’ stress markers within these training environments. The aim of this pilot study was to investigate repetitive stress among healthcare professionals in simulated pre-hospital emergency scenarios using either SIM or SPs. Teams with one emergency medical services (EMS) physician and two paramedics completed three SIM scenarios and two SP scenarios consecutively. To evaluate stress, salivary cortisol and alpha-amylase were measured in saliva samples taken before, during and after the scenarios. A total of 14 EMS physicians (29% female; mean age: 36.8 ± 5.0 years; mean duration of EMS-experience: 9.1 ± 5.8 years) and 27 paramedics (11% female; age: 30.9 ± 6.9 years; EMS experience: 8.1 ± 6.0 years) completed the study. Alpha-amylase and cortisol levels did not differ significantly between the two professions. Cortisol values showed a gradual and statistically significant reduction over time but little change was observed in response to each scenario. In contrast, alpha-amylase activity increased significantly in response to every SIM and SP scenario, but there was no clear trend towards an overall increase or decrease over time. Increases in salivary alpha-amylase activity suggest that both SIM and SP training produce stress among emergency healthcare professionals. Corresponding increases in salivary cortisol levels were not observed. Among physicians in the emergency setting, it appears that alpha-amylase provides a more sensitive measure of stress levels than cortisol.
    Scandinavian Journal of Trauma Resuscitation and Emergency Medicine 04/2015; 23(31). DOI:10.1186/s13049-015-0110-6 · 2.03 Impact Factor
  • Oliver Grottke · Dietmar Fries · Bartolomeu Nascimento
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    ABSTRACT: To provide an overview of acquired coagulopathies that can occur in various perioperative clinical settings. Also described are coagulation disturbances linked to antithrombotic medications and currently available strategies to reverse their antithrombotic effects in situations of severe hemorrhage. Recent studies highlight the link between low fibrinogen and decreased fibrin polymerization in the development of acquired coagulopathy. Particularly, fibrin(ogen) deficits are observable after cardiopulmonary bypass in cardiac surgery, on arrival at the emergency room in trauma patients, and with ongoing bleeding after child birth. Regarding antithrombotic therapy, although new oral anticoagulants offer the possibility of efficacy and relative safety compared with vitamin K antagonists, reversal of their anticoagulant effect with nonspecific agents, including prothrombin complex concentrate, has provided conflicting results. Specific antidotes, currently being developed, are not yet licensed for clinical use, but initial results are promising. Targeted hemostatic therapy aims to correct coagulopathies in specific clinical settings, and reduce the need for allogeneic transfusions, thus preventing massive transfusion and its deleterious outcomes. Although there are specific guidelines for reversing anticoagulation in patients treated with antiplatelet agents or warfarin, there is currently little evidence to advocate comprehensive recommendations to treat drug-induced coagulopathy associated with new oral anticoagulants.
    Current Opinion in Anaesthesiology 04/2015; 28(2):113-22. DOI:10.1097/ACO.0000000000000176 · 1.98 Impact Factor
  • Oliver Grottke · Jerrold H Levy
    Anesthesiology 02/2015; 122(4). DOI:10.1097/ALN.0000000000000608 · 5.88 Impact Factor
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    ABSTRACT: Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 ± 138 ng/ml). Both three- and four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.
    Thrombosis and Haemostasis 01/2015; 113(4). DOI:10.1160/TH14-08-0712 · 4.98 Impact Factor
  • M Honickel · T Braunschweig · J Ryn · R Rossaint · O Grottke
    Critical Care 01/2015; 19(Suppl 1):P351. DOI:10.1186/cc14431 · 4.48 Impact Factor
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    ABSTRACT: Objective: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with chemokine-like functions that plays a role in several inflammatory diseases including atherosclerosis. We recently demonstrated that in addition to macrophages and endothelial cells, platelets are a source of MIF. However, the functional relevance of platelet-derived MIF and differences to other platelet chemokines are unclear. Here, we sought to define the secretion pattern of platelet MIF and to characterize its functional profile in comparison with known atherogenic platelet chemokines. Methods and results: Applying ELISA, we show that MIF is released from thrombin-stimulated platelets after 2 h, whereas CXCL12 and CXCL4 are secreted within minutes. Applied to platelets, MIF, unlike CXCL12, did not enhance platelet activation as analyzed by platelet aggregation, CD62P exposure and chemokine secretion studies. In contrast, both MIF and CXCL12 attenuated ADP-induced calcium transients in platelets. Transmigration and monocyte flow adhesion assays toward conditioned platelet supernatants together with MIF antibody blockade or supernatants from Mif(-/-) mice suggested that platelet-derived MIF has a stronger chemotactic activity than CXCL12 at its respective optimal secretion interval, and showed that platelet MIF substantially contributes to monocyte adhesion on endothelial layers. Moreover, MIF was found to delay clot retraction. Conclusions: We demonstrate that MIF differs from other platelet-derived chemokines by delayed secretion kinetics and by a distinct autocrine/paracrine modulation potential. Importantly, MIF was found to be a major platelet-derived chemotactic recruitment factor with clot-modulating properties and therefore might be relevant in inflammatory diseases such as atherosclerosis.
    Atherosclerosis 12/2014; 239(1). DOI:10.1016/j.atherosclerosis.2014.12.039 · 3.99 Impact Factor
  • Critical care (London, England) 12/2014; 18(3):435. · 4.48 Impact Factor
  • Joanne van Ryn · Oliver Grottke · Henri Spronk
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    ABSTRACT: Dabigatran, a direct thrombin inhibitor, is increasingly used clinically as one of the new oral anticoagulants. This review summarizes the assays available to measure its activity and includes the relative sensitivity of the different assays for this agent. In addition to plasma-based clotting tests, assays commonly used in surgical/emergency settings, such as activated clotting time and thromboelastometry/thromboelastography, are reviewed. In addition, the thrombin generation assay is discussed as an important method to determine the potential risk of thrombosis or bleeding and its relevance to the measurement of direct thrombin inhibitors.
    Clinics in Laboratory Medicine 09/2014; 34(3). DOI:10.1016/j.cll.2014.06.008 · 1.37 Impact Factor
  • European Journal of Anaesthesiology 06/2014; 31:105. DOI:10.1097/00003643-201406001-00289 · 2.94 Impact Factor
  • European Journal of Anaesthesiology 06/2014; 31:97. DOI:10.1097/00003643-201406001-00265 · 2.94 Impact Factor
  • O. Grottke · C. Zentai · H. ten Cate · H. Spronk · R. Rossaint
    European Journal of Anaesthesiology 06/2014; 31:103. DOI:10.1097/00003643-201406001-00284 · 2.94 Impact Factor
  • European Journal of Anaesthesiology 06/2014; 31:95-96. DOI:10.1097/00003643-201406001-00261 · 2.94 Impact Factor
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    ABSTRACT: Background: Fibrinogen concentrate may reduce blood loss after trauma. However, its effect on endogenous fibrinogen synthesis is unknown. The authors investigated the effect of exogenous human fibrinogen on endogenous fibrinogen metabolism in a 24-h porcine trauma model. Methods: Coagulopathy was induced in 20 German Landrace pigs by hemodilution and blunt liver injury. Animals were randomized to receive fibrinogen concentrate (100 mg/kg; infusion beginning 20 min postinjury and lasting approximately 10 min) or saline. Fibrinogen concentration, thromboelastometry, and quantitative reverse transcriptase polymerase chain reaction of fibrinogen genes in liver tissue samples were recorded. Internal organs were examined histologically for emboli. Results: Coagulation parameters were impaired and plasma fibrinogen concentrations were reduced before starting infusion of fibrinogen concentrate/saline. Twenty minutes after starting infusion, exogenous fibrinogen supplementation had increased plasma fibrinogen concentration versus controls (171 ± 19 vs. 63 ± 10 mg/dl [mean ± SD for Multifibren U]; 185 ± 30 vs. 41 ± 4 mg/dl [Thrombin reagent]; P < 0.05 for both comparisons). The between-group difference in plasma fibrinogen concentration diminished thereafter, with maximum concentrations in both groups observed at approximately 24 h, that is, during the acute-phase reaction after trauma. Fibrinogen supplementation did not down-regulate endogenous fibrinogen synthesis (no between-group differences in fibrinogen messenger RNA). Total postinjury blood loss was significantly lower in the fibrinogen group (1,062 ± 216 vs. 1,643 ± 244 ml; P < 0.001). No signs of thromboembolism were observed. Conclusions: Administration of human fibrinogen concentrate did not down-regulate endogenous porcine fibrinogen synthesis. The effect on plasma fibrinogen concentration was most pronounced at 20 min but nonsignificant at approximately 24 h.
    Anesthesiology 05/2014; 121(4). DOI:10.1097/ALN.0000000000000315 · 5.88 Impact Factor

Publication Stats

428 Citations
184.75 Total Impact Points


  • 2015
    • University of Toronto
      Toronto, Ontario, Canada
  • 2007–2015
    • University Hospital RWTH Aachen
      • Department of Neurology
      Aachen, North Rhine-Westphalia, Germany
  • 2009–2014
    • RWTH Aachen University
      • • Institute of Medical Informatics
      • • Virtual Reality Group
      Aachen, North Rhine-Westphalia, Germany