Point-of-care detection and differentiation of anticoagulant therapy - development of thromboelastometry-guided decision-making support algorithms

Abstract

Background: DOAC detection is challenging in emergency situations. Here, we demonstrated recently, that modified thromboelastometric tests can reliably detect and differentiate dabigatran and rivaroxaban. However, whether all DOACs can be detected and differentiated to other coagulopathies is unclear. Therefore, we now tested the hypothesis that a decision tree-based thromboelastometry algorithm enables detection and differentiation of all direct Xa-inhibitors (DXaIs), the direct thrombin inhibitor (DTI) dabigatran, as well as vitamin K antagonists (VKA) and dilutional coagulopathy (DIL) with high accuracy.

Methods: Following ethics committee approval (No 17-525-4), and registration by the German clinical trials database we conducted a prospective observational trial including 50 anticoagulated patients (n = 10 of either DOAC/VKA) and 20 healthy volunteers. Blood was drawn independent of last intake of coagulation inhibitor. Healthy volunteers served as controls and their blood was diluted to simulate a 50% dilution in vitro. Standard (extrinsic coagulation assay, fibrinogen assay, etc.) and modified thromboelastometric tests (ecarin assay and extrinsic coagulation assay with low tissue factor) were performed. Statistical analyzes included a decision tree analyzes, with depiction of accuracy, sensitivity and specificity, as well as receiver-operating-characteristics (ROC) curve analysis including optimal cut-off values (Youden-Index).

Results: First, standard thromboelastometric tests allow a good differentiation between DOACs and VKA, DIL and controls, however they fail to differentiate DXaIs, DTIs and VKAs reliably resulting in an overall accuracy of 78%. Second, adding modified thromboelastometric tests, 9/10 DTI and 28/30 DXaI patients were detected, resulting in an overall accuracy of 94%. Complex decision trees even increased overall accuracy to 98%. ROC curve analyses confirm the decision-tree-based results showing high sensitivity and specificity for detection and differentiation of DTI, DXaIs, VKA, DIL, and controls.

Conclusions: Decision tree-based machine-learning algorithms using standard and modified thromboelastometric tests allow reliable detection of DTI and DXaIs, and differentiation to VKA, DIL and controls.

Trial registration: Clinical trial number: German clinical trials database ID: DRKS00015704 .

Keywords: Direct factor Xa inhibitors; Direct thrombin inhibitors; Direct-acting oral anticoagulants; Thromboelastometry.

Fig. 1

Decision Tree 1 (DT1) includes standard thromboelastometric tests (EXTEM, FIBTEM, HEPTEM, INTEM). Overall classification accuracy is 78%. Percentage in boxes display the portion of included samples at this stage. CON: control; DIL: dilutional coagulopathy; VKA: vitamin K antagonist (phenprocoumon); DTI: direct thrombin inhibitor (dabigatran); DXaI: direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban)

Fig. 2

Decision Tree 2 (DT2) includes standard and new thromboelastometric tests (FIBTEM, TFTEM, ECATEM). Overall classification accuracy is 94%. Percentage in boxes display the portion of included samples at this stage. CON: control; DIL: dilutional coagulopathy; VKA: vitamin K antagonist (phenprocoumon); DTI: direct thrombin inhibitor (dabigatran); DXaI: direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban)

Fig. 3

Decision Tree 3 (DT3) includes standard and new thromboelastometric tests (FIBTEM, HEPTEM, TFTEM, ECATEM). Overall classification accuracy is 98%. Percentage in boxes display the portion of included samples at this stage. CON: control; DIL: dilutional coagulopathy; VKA: vitamin K antagonist (phenprocoumon); DTI: direct thrombin inhibitor (dabigatran); DXaI: direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban)