Electrochemical Monitoring in Anticoagulation Therapy

Abstract

The process of blood coagulation, wherein circulating blood transforms into a clot in response to an internal or external injury, is a critical physiological mechanism. Monitoring this coagulation process is vital to ensure that blood clotting neither occurs too rapidly nor too slowly. Anticoagulants, a category of medications designed to prevent and treat blood clots, require meticulous monitoring to optimise dosage, enhance clinical outcomes, and minimise adverse effects. This review article delves into the various stages of blood coagulation, explores commonly used anticoagulants and their targets within the coagulation enzyme system, and emphasises the electrochemical methods employed in anticoagulant testing. Electrochemical sensors for anticoagulant monitoring are categorised into two types. The first type focuses on assays measuring thrombin activity via electrochemical techniques. The second type involves modified electrode surfaces that either directly measure the redox behaviours of anticoagulants or monitor the responses of standard redox probes in the presence of these drugs. This review comprehensively lists different electrode compositions and their detection and quantification limits. Additionally, it discusses the potential of employing a universal calibration plot to replace individual drug-specific calibrations. The presented insights are anticipated to significantly contribute to the sensor community's efforts in this field.

Keywords: anticoagulants; coagulation; electrochemical sensors; factor Xa; point of care; thrombin.

Figure 2

A schematic representation showing the sites of action of different anticoagulants. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) both bind to antithrombin-III (AT-III), resulting in a complex that is capable of inhibiting thrombin, factor Xa, TF-VIIa, factor IXa, factor XIa, and factor XIIa (highlighted in yellow) [35]. Vitamin K antagonists act as anticoagulants by inhibiting the synthesis of the active versions of four vitamin K-dependent procoagulant factors, including VII, IX, X, and prothrombin (highlighted in green) [36].

Figure 1

A schematic representation of the blood coagulation cascade. The plasma clotting reactions consist of two mechanisms: the intrinsic and extrinsic pathways. The extrinsic pathway is initiated by vascular injury and subsequent tissue factor (TF) exposure in the blood plasma. The formation of thrombin can activate the intrinsic pathway, which further activates FXI. Both pathways converge at the FXa formation, which produces a burst of thrombin at the end, converting fibrinogen to fibrin with the simultaneous activation of the platelets, resulting fibrin clot, which arrests blood loss.

Figure 3

A photo of a disposable strip with gold co-facing electrodes (left) and a schematic diagram of co-facing gold disposable electrodes used for DOAC quantification (right). For the thrombin inhibitor assay, thrombin is used as an enzyme, and the substrate is Tos-Gly-Pro-Arg-ACP. Meanwhile, for the FXa inhibitor assay, FXa is used to measure the anticoagulant concentration using the Cbz-D-Arg-Gly-Arg-ACP substrate. WE = working electrode, CE = counter electrode, and pseudo-RE = Au pseudo-reference electrode. Adapted from references [56,57,58].

Figure 4

Schematic representation of molecularly imprinted polymer-modified electrodes before (top) and after (bottom) anticoagulant binding.