Relative effects of different non-vitamin K antagonist oral anticoagulants on global thrombotic status in atrial fibrillation

This is an Accepted Manuscript of an article published by Taylor & Francis GroupNon-vitamin K antagonist oral anticoagulants (NOACs) reduce the risk of thromboembolism in patients with atrial fibrillation (AF). There has been no head-to-head comparison of the effect of these agents on ex vivo thrombotic and thrombolytic status. Enhanced platelet reactivity and impaired endogenous thrombolysis are risk factors for recurrent thrombotic events. We aimed to assess the comparative effect of NOACs and warfarin using an ex vivo test of thrombosis and thrombolysis. Eighty patients with newly diagnosed non-valvular AF were tested before, and after being established on apixaban (n = 20), dabigatran (n = 20), rivaroxaban (n = 20), or warfarin (n = 20). Thrombotic status was assessed with the automated, point-of-care Global Thrombosis Test (GTT) that assesses both platelet reactivity and endogenous thrombolysis from native blood. The time taken to form an occlusive thrombus (occlusion time, OT) and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured. All anticoagulants caused OT prolongation compared to baseline (apixaban 403 ± 102s vs. 496 ± 125s, p = 0.006; dabigatran 471 ± 106s vs. 656 ± 165s, p < 0.00001; rivaroxaban 381 ± 119s vs. 579 ± 158, p < 0.00001; warfarin 420 ± 145s vs. 604 ± 124s, p < 0.00001). Apixaban reduced LT from baseline (1895[1702-2167]s vs. 1435[347-1990]s; p = 0.006). A trend for LT reduction was seen with other NOACs (dabigatran 1594[1226-2069]s vs. 1539[561-2316]s, p = 0.499; rivaroxaban 2085[1366-2428]s vs. 1885[724-2420]s, p = 0.295) but not with warfarin (1490[1206-1960]s vs. 1776[1545-2334], p = 0.601). Our results suggest that NOACs and warfarin have a similar favorable effect on reducing platelet reactivity. All NOACs exhibited a trend toward enhancing endogenous thrombolytic status, although this was significant only for apixaban. This raises the possibility of using NOACs to enhance impaired endogenous fibrinolysis in patients at high-thrombotic risk.Peer reviewedFinal Accepted Versio

Catheter ablation for AF improves global thrombotic profile and enhances fibrinolysis

© The Author(s) 2017. This article is an open access publication. The final authenticated version is available online at: https://doi.org/10.1007/s11239-017-1548-3Patients with atrial fibrillation (AF) are at increased risk of thrombotic events despite oral anticoagulation (OAC). Radiofrequency catheter ablation (RFCA) can restore and maintain sinus rhythm (SR) in patients with AF. To assess whether RFCA improves thrombotic status. 80 patients (71% male, 64 ± 12y) with recently diagnosed AF, on OAC and scheduled to undergo RFCA or DC cardioversion (DCCV) were recruited. Thrombotic status was assessed using the point-of-care global thrombosis test (GTT), before, and 4-6 weeks after DCCV and 3 months after RFCA. The GTT first measures the time taken for occlusive thrombus formation (occlusion time, OT), while the second phase of the test measures the time taken to spontaneously dissolve this clot through endogenous thrombolysis (lysis time, LT). 3 months after RFCA, there was a significant reduction in LT (1994s [1560; 2475] vs. 1477s [1015; 1878]) in those who maintained SR, but not in those who reverted to AF. At follow-up, LT was longer in those in AF compared to those in SR (AF 2966s [2038; 3879] vs. SR 1477s [1015; 1878]). RFCA resulted in no change in OT value, irrespective of rhythm outcome. Similarly, there was no change in OT or LT in response to DCCV, irrespective of whether SR was restored. Successful restoration and maintenance of SR following RFCA of AF is associated with improved global thrombotic status with enhanced fibrinolysis. Larger studies are required to confirm these early results and investigate whether improved thrombotic status translates into fewer thromboembolic events.Peer reviewedFinal Published versio

Thrombotic status of patients with atrial fibrillation

BACKGROUND Atrial fibrillation (AF) is associated with increased risk of thrombosis. It is still not fully understood whether AF contributes to only a local prothrombotic state (in the left atrium) or whether this is a systemic phenomenon. Furthermore, it is not known whether restoration of sinus rhythm (SR) with cardioversion or catheter ablation can decrease thrombotic risk over and above that achieved with anticoagulation. The aim of my thesis was to assess the effect of restoration of sinus rhythm on thrombotic status in patients with AF. METHODS We assessed thrombotic status, both peripherally and in the cardiac chambers, in patients with different arrhythmias undergoing radiofrequency catheter ablation (RFCA) with blood samples drawn from the femoral vein and both atria (if applicable). In another study, we investigated the effect of direct current cardioversion (DCCV) and RFCA on global thrombotic status. The peripheral samples were drawn before and 4-6 weeks after DCCV and 3 months after RFCA. The effect of different types of anticoagulation, namely vitamin K antagonist and non-vitamin K oral anticoagulants, on thrombotic status was also assessed. Thrombotic status was assessed with highly physiological, point-of-care Global Thrombosis Test (GTT), which assesses both platelet reactivity (time taken to form an occlusive thrombus - occlusion time, OT) and endogenous thrombolysis (time taken to restore blood flow in the testing column – lysis time, LT) using a native, non-anticoagulated blood sample. RESULTS There were no significant differences in thrombotic status between intra-cardiac and peripheral blood in patients undergoing RFCA. In particular, left atrial blood samples were not more pro-thrombotic than peripheral blood samples in patients with AF. Successful restoration and maintenance of SR with RFCA led to normalization of fibrinolytic profile (as shown by decrease in LT: LT before RFCA: 1994s [1560; 2475] vs. LT after RFCA: 1477s [1015; 1878]; p<0.001). This was not seen following DCCV. Interestingly, recurrence of AF after DCCV or RFCA resulted in deterioration of thrombotic status (increase in LT), (LT before DCCV: 1819s [1453; 2208] vs. LT after DCCV: 2156s [1784; 2332]; p=0.009). Anticoagulation led to significantly enhanced occlusion time with the most significant change observed in response to rivaroxaban (OT before anticoagulation: 353s [311; 482] vs. OT on anticoagulation: 552s [464; 725]; p=0.000089). Although a similar trend was seen with all NOAC, only apixaban had a favourable effect on fibrinolysis (decrease in LT), (LT before anticoagulation: 1848s [1675; 2166] vs. LT after anticoagulation: 1471s [361; 1993]; p=0.009). Among patient taking oral anticoagulants, a short LT, with rapid endogenous fibrinolysis, with a cut-point of 1346 s, was predictive of future bleeding events with the specificity of 82% and sensitivity of 72%. Combining the LT with the HASBLED score increased specificity to 94.6%, while reducing sensitivity to 50%. CONCLUSION Patients with AF appear to have a prothrombotic state that is not confined to the left atrium. Oral anticoagulation significantly reduced platelet reactivity, and demonstrated a trend to improved endogenous fibrinolysis. Restoration of SR in patients with AF, using RFCA, appears to exert a favourable effect on thrombotic status in AF patients, over and above that of anticoagulation. Rapid endogenous fibrinolysis with short LT on anticoagulation may be useful to predict bleeding in patients with AF. Further studies are required to validate these results in larger cohorts.Open Acces

Impaired thrombolysis : a novel cardiovascular risk factor in end-stage renal disease

End-stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Prothrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) and thrombolytic status, may identify vulnerable patients. Our aim was to assess overall thrombotic status in ESRD and relate this to cardiovascular risk.Peer reviewe