Global Thrombosis Test (GTT) can detect major determinants of haemostasis including platelet reactivity, endogenous fibrinolytic and thrombin generating potential

Abstract

Detection of both thrombosis and bleeding risk are essential in clinical cardiology. Thrombin generated by activated platelets and from the extrinsic coagulation pathway is the major determinant of thrombogenesis and hemostasis. Although novel oral anticoagulants further increase the bleeding risk of antiplatelet drugs, platelet function tests do not reliably predict hemorrhagic complications. It seems that in addition to platelet aggregation, true assessment of bleeding risks requires the measurement of both platelet and plasma derived thrombin activity. To adapt a novel, near-patient test for the assessment of both antithrombotic and anticoagulant effects of oral thrombin inhibitors. The point-of-care Global Thrombosis Test (GTT), which measures platelet reactivity to shear-activation in native blood, was used. Thrombin, generated from activated platelets (procoagulant activity) plays a pivotal role in GTT measurement. In order to assess endogenous thrombin potential, in a separate blood sample thrombin generation was induced by microparticles formed during hypotonic hemolysis. Thus two blood samples were tested to measure simultaneously platelet reactivity (occlusion time, OT) and hemolysis (microparticles)-induced endogenous thrombin potential (OT-H). In healthy subjects (n=32), OT measured in native blood was reduced in hemolysed blood (100% vs. 43 ± 4%; OT vs. OT-H respectively). Shortening of OT in hemolysed blood (OT-H) was dose-dependently inhibited by the in vitro added thrombin inhibitor argatroban. In patients receiving dabigatran (n=27), OT and, to a lesser extent, OT-H was prolonged, compared to healthy volunteers. Intra-assay variation of OT-H was low (4.5%), but interindividual variation was great, both in healthy subjects (61%) and in patients on dabigatran (65%). Thrombin inhibitors argatroban, heparin (in vitro) and dabigatran (in vivo) all prolonged both OT and OT-H. There was no correlation between the measured OT and OT-H data. Microparticles shed from erythrocytes during hypotonic lysis of native blood considerably shortened OT. In a direct proportion to the applied concentrations, various thrombin inhibitors prolonged both OT (antithrombotic effect) and to a lesser extent, OT-H (anticoagulant effect). Further large studies are required to evaluate the usefulness of this technique in a clinical setting, in assessing the anticoagulant and antithrombotic effects of medication and relating GTT results with observed thrombotic and bleeding events.