AG Hemostaseology and Transplantation
PD Dr. med. Hendrik Eismann, Dr. med. Lion Sieg
Perioperative bleeding is common and poses a significant risk to patients both in the operating theater and in the intensive care unit. The management of expected and unexpected bleeding is a particular challenge for anesthesiologists, surgeons and hemostaseologists, as there is a lack of clear transfusion triggers and transfusion targets.
In addition, the causes of bleeding are often unknown or cannot be determined promptly due to a lack of suitable diagnostics. The correct selection and use of blood products and components perioperatively is therefore difficult and the clinical effect and side effects cannot always be assessed.
Economic aspects also play a not insignificant role. In this context, the functional correlations and also the informative value in diagnostics and therapy, especially in transplantations, are still little known or evaluated.
Our main objectives are
- Identification of pathological changes in hemostasis perioperatively, including in the intensive care unit
- Identification of mechanisms and correlations in hemostasis disorders and effects of therapeutics
- Application, establishment and evaluation of "point of care" procedures to improve coagulation diagnostics and therapy
- Development/ and establishment of experimental functional models
Projects
The MHH is one of Europe's leading transplant centers, performing well over 100 liver transplants every year.
The anesthesiological procedure for liver transplantation is complex and includes, among many other factors, coagulation management in particular. The hemostasis potential of patients is often significantly limited due to previous illnesses, loss and consumption during the surgical procedure and other pathophysiological changes such as hypothermia, acidosis or hyperfibrinolysis.
Both the differentiation and delineation of the predominant cause of bleeding in a hemorrhage as well as the monitoring of any therapy is difficult, especially in the acute situation, and is increasingly carried out using point-of-care (POC) procedures such as rotational thrombelastometry in addition to the determination of classic coagulation parameters. In addition to rapid availability, information on clot formation and clot strength can also be collected over time in addition to thrombin generation.
In this environment, we want to characterize the diagnostic and therapeutic measures clinically and functionally and assess their benefits.
On the one hand, clinical and therapeutic data will be collected prospectively during the operation and, on the other hand, various in vitro approaches will be carried out with the aim of being able to better predict the effect of factor therapy, for example.
At the same time, plasma aliquots are prepared from the sample remnants and frozen for further investigations, e.g. using flow cytometry and FlowChamber.
Comparison between three fully automatic devices (ROTEM Sigma®, TEG 6s®, Quantra®) and one semi-automatic device (Clot Pro®) for viscoelastic or ultrasound-guided whole blood coagulation measurement in surgical, intensive care and emergency patients.
Background
In severely injured patients, patients with major blood loss during surgery and patients in intensive care with coagulation disorders, one of the four devices available on the market for viscoelastic or ultrasound-guided coagulation measurement is often used as a point of care diagnostic. To date, there is no clinical comparison of the degree of agreement of the measurement results, the time to results and the handling times of all four test procedures available on the market.
Objective
To determine the degree of agreement between the results of the respective comparable measurement approaches (fibrinogen clot, approach, extrinsic approach and intrinsic approach with heparinase) of the individual devices. Check the correlation of the measurement results with clinical laboratory values (platelets, fibrinogen level according to Clauss) of the patients.
The Xenotransplantation Research Unit has been continuously funded by the DFG since 2004 as 1 of 9 sub-projects of the Transregional Research Unit FOR 535. The research group under the direction of M. Winkler (Visceral Surgery) A. Tiede (Hemostaseology) and L. Friedrich (Anesthesiology) is working on a multidisciplinary basis and is investigating the xenogenic activation of the human blood coagulation system in ex vivo xeno-perfused pig kidneys in large animal experiments.
For this purpose, an extracorporeal perfusion circuit has been established in which coagulation activation in human blood can be imaged after contact with porcine renal endothelium.
Work program and goals:
In the current application period, we are working on the analysis of endothelial cell activation in xenoperfused tissue and the interactions between endothelial cells, blood cells and the coagulation system under pharmacological influence (e.g. rhATIII, TFPI, rh-aPC). At the same time, the constructs of genetically modified pigs (e.g. hTFPI, h-HO-1, h-HTM) are tested for expression and function in our system. These animals are generated in other subprojects of the Transregional Research Unit.
Background
Twenty-five to 85% of trauma patients are under the influence of alcohol in addition to experiencing injury-related coagulation impairment. Viscoelastic point-of-care tests (thrombelastography [TEG], rotational thromboelastometry [ROTEM]) are popular tools for rapid hemostasis assessment and therapeutic decision-making in this and other settings. While alcohol affects these tests in-vitro, their specific effects in-vivo are unclear. Therefore, we evaluated the effects of alcohol ingestion on ROTEM parameters.
Methods
Twenty volunteers provided informed consent to drinking red wine, whisk(e)y, or vodka to a target blood alcohol concentration of 1 ‰ within one hour, calculated with the Widmark formula. Blood samples were collected before drinking, at a breath alcohol concentration of 0.5 ‰, and at 1.0 ‰, but no later than one hour. After each blood collection, ExTEM and FibTEM tests were performed directly "at the bedside."
Results
All participants had a blood alcohol concentration (BAC) of 0.00 ‰ at the beginning. The mean BACs at the second and third collection were 0.48 and 0.76 ‰, respectively. There were no significant differences in the ExTEM parameters. FibTEM measurements showed a significant difference at the A10 value (13.0 vs. 14.0 mm, P = 0.014) and a trend at the maximum amplitude (maximum clot firmness [MCF] 13.7 vs. 16.2 mm, P = 0.075). We saw no significant differences in fibrinolysis parameters and no hyperfibrinolysis in our ROTEM measurements.
Conclusions
Ethanol ingestion can impair early fibrin polymerization. These results might be of special relevance in trauma and support routine application of ROTEM/TEG in such cases.
This prospective non-interventional observational study was conducted together with the Hematology and Trauma Surgery departments with the aim of comparing different hemostaseological examinations in patients with severe polytrauma (ISS > 15).
For this purpose, 53 patients were closely monitored hemostaseologically for 48 hours after admission, and hemostasis-relevant therapies and numerous clinical data were collected. It was investigated whether and how clinical and hemostaseological findings correlate, also with regard to the respective potential.
Cooperation
Our working group maintains numerous collaborations and contacts with internal working groups and other departments at MHH.
Of particular note are the working groups "Translational Perioperative Inflammation Research", "Applied Hemotherapy, Hematology" and the Clinical Department of General, Visceral and Transplant Surgery.
Furthermore, there is a close cooperation with Dr. med. Kai Johanning (Chief Physician Anaesthesia, Clinic in Bielefeld) and Dr. med. Carsten Schumacher (Senior physician ECTU, Center for Clinical Trials (ZKS) of the MHH).
- We would like to thank all our partners for their excellent cooperation.
Publications
- Beetz O, Oldhafer F, Weigle CA, Cammann S, DeTemple D, Sieg L, Eismann H, Palmaers T, Vondran FWR. Porcine Liver Transplantation Without Veno-venous Bypass As an Extended Criteria Donor Model. J Vis Exp. 2022 Aug 17;(186). doi: 10.3791/64152. PMID: 36063020.
- Beetz O, Cammann S, Weigle CA, Sieg L, Eismann H, Johanning K, Falk CS, Krech T, Oldhafer F, Vondran FWR. Interleukin-18 and High-Mobility-Group-Protein B1 are Early and Sensitive Indicators for Cell Damage During Normothermic Machine Perfusion after Prolonged Cold Ischemic Storage of Porcine Liver Grafts. Transpl Int. 2022 Oct 20;35:10712. doi: 10.3389/ti.2022.10712. PMID: 36338535; PMCID: PMC9630326
- Oldhafer F, Wittauer EM, Beetz O, Weigle CA, Sieg L, Eismann H, Braubach P, Bock M, Jonigk D, Johanning K, Vondran FWR. Supportive Hepatocyte Transplantation after Partial Hepatectomy Enhances Liver Regeneration in a Preclinical Pig Model. Eur Surg Res. 2021;62(4):238-247. doi: 10.1159/000516690. Epub 2021 May 27. PMID: 34044396.
- Eismann H, Sieg L, Ahmed H, Teske J, Behrendt P, Friedrich L, Schumacher C, Johanning K. Influence of alcohol consumption on blood coagulation in rotational thromboelastometry (ROTEM): an in-vivo study. Korean J Anesthesiol. 2020 Aug;73(4):334-341. doi: 10.4097/kja.20071. Epub 2020 Apr 16. PMID: 32299155; PMCID: PMC7403120.
- Wittauer EM, Oldhafer F, Augstein E, Beetz O, Kleine M, Schumacher C, Sieg L, Eismann H, Johanning K, Bleich A, Vondran FWR. Porcine model for the study of liver regeneration enhanced by non-invasive 13C-methacetin breath test (LiMAx test) and permanent portal venous access. PLoS One. 2019 May 31;14(5):e0217488. doi: 10.1371/journal.pone.0217488. PMID: 31150446; PMCID: PMC6544243.
- Ramackers W, Werwitzke S, Klose J, Friedrich L, Johanning K, Bergmann S, Klempnauer J, Winkler M, Tiede A. Investigation of the influence of xenoreactive antibodies on activation of complement and coagulation in an ex vivo perfusion animal study using porcine kidneys. Transpl Int. 2019 May;32(5):546-556. doi: 10.1111/tri.13396. Epub 2019 Jan 22. PMID: 30597634.
- Schumacher C, Eismann H, Sieg L, Friedrich L, Scheinichen D, Vondran FWR, Johanning K. Preoperative Recipient Parameters Allow Early Estimation of Postoperative Outcome and Intraoperative Transfusion Requirements in Liver Transplantation. Prog Transplant. 2018 Jun;28(2):116-123. doi: 10.1177/1526924818765805. Epub 2018 Mar 20. PMID: 29558874.
- Schumacher C, Eismann H, Sieg L, Friedrich L, Scheinichen D, Vondran FWR, Johanning K. Use of Rotational Thromboelastometry in Liver Transplantation Is Associated With Reduced Transfusion Requirements. Exp Clin Transplant. 2019 Apr;17(2):222-230. doi: 10.6002/ect.2017.0236. Epub 2018 Oct 5. PMID: 30295585.
- Vondran FW, Schumacher C, Johanning K, Hartleben B, Knitsch W, Wiesner O, Jaeckel E, Manns MP, Klempnauer J, Bektas H, Lehner F. Application of the Liver Maximum Function Capacity Test in Acute Liver Failure: A Helpful Tool for Decision-Making in Liver Transplantation? Case Rep Transplant. 2016;2016:7074636. doi: 10.1155/2016/7074636. Epub 2016 May 4. PMID: 27274881; PMCID: PMC4870360.
- Ramackers W, Friedrich L, Klose J, Vondran F, Bergmann S, Schüttler W, Johanning K, Werwitzke S, Trummer A, Bröcker V, Klempnauer J, Winkler M, Tiede A. Recombinant human antithrombin prevents xenogenic activation of hemostasis in a model of pig-to-human kidney transplantation. Xenotransplantation. 2014 Jul-Aug;21(4):367-75. doi: 10.1111/xen.12104. Epub 2014 May 8. erratum in: Xenotransplantation. 2015 Jul-Aug;22(4):328. PMID: 24807299.