Effects of non-vitamin K antagonist oral anticoagulants on fibrin clot and whole blood clot formation, integrity and thrombolysis in patients with atrial fibrillation

Abstract

Non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin and heparins in several clinical situations. With varying modes of action, the effects of NOACs on thrombus formation, integrity, and lysis is unknown. To determine whether two techniques of thrombelastography (TEG) and a micro-plate assay (MPA) provide novel data on thrombus formation, integrity and lysis in those taking a NOACs compared to warfarin and a control group taking aspirin. We assessed thrombogenesis, clot integrity and fibrinolysis in blood (TEG) and plasma (MPA) from 182 atrial fibrillation patients—50 on aspirin, 50 on warfarin, and 82 on a NOAC (17 apixaban, 19 dabigatran and 46 rivaroxaban). Eleven of 16 TEG indices and 4 of 5 MPA indices differed (p ≤ 0.01) between those on aspirin, warfarin or a NOAC. Three TEG indices and 4 MPA indices differed (p < 0.01) between the NOACs. Time to initiation of clot formation was most rapid on apixaban, then rivaroxaban and slowest on dabigatran. The rate of clot formation was most rapid on dabigatran, then apixaban, and slowest on rivaroxaban. Clot density was greatest on rivaroxaban, then apixaban, but weakest on dabigatran. The rate of clot dissolution was most rapid in apixaban, then dabigatran, and slowest on rivaroxaban. The TEG and MPA identify major differences in thrombogenesis and fibrinolysis in different NOACs. These techniques may have value in investigating the effects of these drugs on haemostasis in a clinical setting, and in identifying those in need of targeted therapy.

Apixaban enhances endogenous fibrinolysis in patients with atrial fibrillation

“…Whilst some small studies reported that apixaban had minimal effect on TEG parameters, and that for the patients on apixaban, mean R value was within reference range representative of a normal population, 16 others have shown that spiking of blood with apixaban in vitro increased R time and time to maximal thrombus growth and coagulation, 17 prolonged clotting time and time to maximum velocity 18 . In the largest study assessing patients with NVAF with TEG, patients taking NOAC developed clot that was quicker to lyse than patients taking warfarin, and the rate of clot dissolution was faster in those on apixaban than in rivaroxaban, with 11 of 16 TEG indices showing a difference between those on aspirin, warfarin, or a NOAC 19 …”

Effect of anticoagulants on fibrin clot structure: A comparison between vitamin K antagonists and factor Xa inhibitors

“…Unlike warfarin, DOACs can be administered at fixed doses, thus reducing the number of hospital visits for drug monitoring. 10,11 Previous studies have shown that fibrin clot structure is abnormal in individuals with thrombotic conditions, and individuals with with postthrombotic syndrome and recurrent venous thromboembolism (VTE) patients have denser clots with thinner fibers that are resistant to fibrinolysis. 12 In addition, clots from individuals with deep vein thrombosis were also shown to be thinner, less porous, and more resistant to lysis.…”

“…Anticoagulants, including warfarin and DOACs, have been shown to alter fibrin clot structure by increasing clot porosity and altering clot density. 11,14,15 Direct thrombin inhibitors have also been shown to delay thrombin generation and increase clot permeability. 16,17 In addition, anticoagulants have been shown to delay clotting lag time and increase the efficiency of clot lysis.…”

Straight to the heart: Pleiotropic antiarrhythmic actions of oral anticoagulants

“…The past decade or so has brought forth a new group of oral therapeutic agents which directly inhibit activated thrombin and FXa, and which are increasingly preferred over the coumarin-derivatives. Besides a more controlled anticoagulation, the newer agents also possess favorable effects on fibrin clot formation and fibrinolysis [13,14]. Currently available DOAC comprise the so-called xabans (rivaroxaban, apixaban, edoxaban) which target FXa, and the gatrans (to date only dabigatran) which inhibit thrombin.…”