Dr. med. Daniel Dirkmann (University Hospital Essen – Department of Anaesthesiology and Intensive Care Medicine), an expert user of the ROTEM® delta and ROTEM® sigma kindly agreed to give us an interview to share his thoughts about our new ROTEM® sigma cartridges with you.
The University Hospital Essen is considered to be a pioneer in coagulation management, installed the first ROTEM® sigma in Germany and are currently equipped with 17 ROTEM® devices.
Which impact does heparin have on blood coagulation?
The major part of the anticoagulant effect of unfractionated heparin is exerted by its binding to antithrombin III (AT III). The latter plasma serine protease is capable of inactivating coagulation factors IIa (thrombin), Xa, and IXa. Heparin binding to AT III results in a conformational change in AT III, increasing its binding to the aforementioned coagulation factors, thus potentiating its effects. While both, low and high molecular weight heparins inhibit factor Xa, only longer chain molecules inhibit thrombin. Besides this, heparin exerts another anticoagulant effect, mediated by another cofactor, heparin cofactor II. This effect is inherent to longer chain molecules and independent of the presence of AT III but needs higher heparin concentrations, and is specific to thrombin, only. Furthermore, heparin has been demonstrated to exert effects on the tissue factor pathway inhibitor and to stimulate fibrinolysis.
In which clinical situations is the influence of heparin particularly strong and what does this mean for the blood coagulation diagnostics in the POC area?
Cardiac surgical procedures with cardio pulmonary bypass (CPB) require anticoagulation in order to prevent clot formation in the bypass circuit. Unfractionated heparin is the most commonly used anticoagulant in this setting. Typically, 300 – 400 U/kg of heparin ± additional heparin in the pump-prime is given as an initial dose. The latter dosing normally resulting in heparin concentrations close to 5 IU/ml about 5 minutes after heparin administration. Monitoring of heparinization is mostly performed using activated clotting time (ACT) assays and ACT values of >400 seconds are commonly considered to provide adequate anticoagulation during CPB. While ACT assays are designed to provide correlation to the blood or plasma heparin concentration over a large range of heparin concentrations the most frequently used coagulation assays, commonly refered to as standard laboratory tests (SLTs), (e.g., prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen concentration) are strongly affected by heparin. Accordingly, these assays are worthless when high concentrations of heparin are used, like in procedures involving CPB. For this reason, and because of their unfavorable long turn-around times, SLTs are only very seldomly used intraoperatively, in cardiac surgery. In contrast, using viscoelastic assays on the ROTEM® delta and sigma enables to assess alternative measures for platelet count and fibrinogen concentration while still under full heparinization.
What is the main difference between the original and the new ROTEM® sigma cartridge? Do you consider the development of the new ROTEM® sigma cartridges to be a useful improvement? Which advantages are offered?
In the original ROTEM® sigma cartridge, results of both extrinsically activated assays (i.e., EXTEM and FIBTEM)* were insensitive to heparin concentrations of approximately 3 IU/ml. Although, this should obviously be unproblematic in most clinical settings, it has relevant implications for its use in cardiac surgery. When using the wide spread approach of performing ROTEM® analyzes before termination of the cardio-pulmonary bypass and thus prior to protamine administration (for example after declamping of the aorta), heparin concentrations have to be expected to markedly exceed 3 IU/ml. Accordingly, when compared to the corresponding assays run on a ROTEM® delta device using liquid reagents, significant effects on ROTEM® variables were seen. Besides the clotting times, especially early clot firmness variables (e.g., A5 and A10), which are commonly used in algorithms for coagulation management were markedly affected. In contrast to the original ROTEM® sigma cartridge, the liquid reagents made the respective assays of the ROTEM® delta insensitive for heparin concentrations of approximately 5 IU/ml. Now, with the new cartridge, heparin insensitivity is provided for 5 IU/ml, with the ROTEM® sigma as well. Accordingly, cardiac surgery units may implement the ROTEM® sigma without making changes in their algorithms.
Do you have any wishes for further developments on the ROTEM® sigma cartridge?
The direct oral anticoagulants (DOACs) (i.e., Dabigatran, Rivaroxaban, Apixaban, and Edoxaban) are increasingly being used in patients with atrial fibrillation and venous thrombosis. Although routine monitoring of their anticoagulant effects is not recommended, it seems relevant to rapidly identify patients on DOACs in emergency situations. Although, plasmatic coagulation assays are affected by the DOACs, these alterations are not as specific as to identify on which drug a patient is and if there is a relevant plasma concentration, justifying the use of a reversal agent. Accordingly, a cartridge providing assays allowing for the rapid and specific detection of direct oral anticoagulants seems to be desirable.
What are your wishes for the ROTEM® sigma?
Now, that viscoelastic testing is automated, I would like to have automatic platelet function testing. Since platelet function testing based on viscoelastic assays has not proven to be helpful, automated impedance aggregometry seems most promising.
* Remark of Tem International GmbH: The same is true for APTEM in the ROTEM® sigma complete cartridge.]