Maria Niespialowska-Steuden

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

AIMS 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. METHODS AND RESULTS Thrombotic and thrombolytic status of ESRD patients (n = 216) on haemodialysis was assessed using the Global Thrombosis Test. This novel, near-patient test measures the time required to form (OT) and time required to lyse (lysis time, LT) an occlusive platelet thrombus. Patients were followed-up for 276 ± 166 days for major adverse cardiovascular events (MACE, composite of cardiovascular death, non-fatal MI, or stroke). Peripheral arterial or arterio-venous fistula thrombosis was a secondary endpoint. Occlusion time was reduced (491 ± 177 vs. 378 ± 96 s, P < 0.001) and endogenous thrombolysis was impaired (LT median 1820 vs.1053 s, P < 0.001) in ESRD compared with normal subjects. LT ≥ 3000 s occurred in 42% of ESRD patients, and none of the controls. Impaired endogenous thrombolysis (LT ≥ 3000 s) was strongly associated MACE (HR = 4.25, 95% CI = 1.58-11.46, P = 0.004), non-fatal MI and stroke (HR = 14.28, 95% CI = 1.86-109.90, P = 0.01), and peripheral thrombosis (HR = 9.08, 95% CI = 2.08-39.75, P = 0.003). No association was found between OT and MACE. CONCLUSION Impaired endogenous thrombolysis is a novel risk factor in ESRD, strongly associated with cardiovascular events.

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

Abstract Non-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.

Catheter ablation for AF improves global thrombotic profile and enhances fibrinolysis

Patients 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.

NOAC BUT NOT VKA FAVORABLY AFFECT ENDOGENOUS THROMBOLYTIC STATUS: A NOVEL MECHANISM OF ACTION

Patients with atrial fibrillation (AF) are at increased risk of stroke through thrombus formation. The propensity for thrombus formation is determined by the balance between prothrombotic factors and endogenous thrombolysis. Endogenous thrombolytic status is frequently impaired in patients with

NOAC in acute coronary syndrome and AF

Cardiovascular disease remains a major cause of morbidity and mortality in developed countries. New treatments, in the form of novel oral anticoagulants (NOAC) that reduce thrombotic risk are now available for patients with atrial fibrillation (AF) or acute coronary syndrome (ACS). Warfarin has been the cornerstone of thromboprophylaxis in patients with AF, but treatment is cumbersome, inconvenient and often unreliable, with fluctuating time in therapeutic range. Thrombotic events also continue to occur in a significant number of ACS patients despite antiplatelet therapy. Thus there is an unfilled need to reduce thrombotic events in ACS and AF patients. NOAC comprise direct factor Xa inhibitors (apixaban, rivaroxaban, darexaban, edoxaban), direct thrombin inhibitors (dabigatran) and PAR-1 antagonists (vorapaxar, atopaxar). In this review, we compare and contrast NOACs and review their individual and specific clinical trial database in ACS and AF. In the setting of ACS, the role of NOAC is unclear, as any reduction in ischemic events appears to be offset by hemorrhagic risk. However, NOAC have a definite place in the treatment of patients with non-valvular AF, where they are at least as effective, if not superior to warfarin.

15 Differential Effects of NOAC and VKA on in Vitro Test of Global Thrombotic Status

Introduction The outcome of a thrombotic trigger, namely whether lasting vessel occlusion occurs or not, is determined the balance between prothrombotic properties of blood and endogenous thrombolysis. Atrial fibrillation (AF) is a major cause of stroke. Patients affected by AF are known to have enhanced thrombotic tendency. In our study we assessed the effect of novel oral anticoagulants (NOAC) and vitamin K antagonists (VKA) on global thrombotic status. Methods Patients with AF were tested to assess global thrombotic status before and during treatment with NOAC (dabigatran n = 12, rivaroxaban n = 9) and VKA (n = 13). Thrombotic status was assessed using the point-of-care Global Thrombosis Test (GTT). This technique utilises non-anticoagulated blood and assesses the time required for thrombus formation, occlusion (OT) and the time required for endogenous thrombolysis to occur, lysis time (LT). Results Compared to baseline, NOAC therapy resulted in a significant prolongation of OT [median 483s (25th–75th %ile: 395–556) vs. 714s (553–842), P < 0.0001] and reduction of LT [1519s (1137–1927) vs. 724s (280–1592), P = 0.032]. Compared to baseline, VKA also prolonged OT [437s (313–550) vs. 639s (575–644), P = 0.007], with no significant effect on LT [1490s (1386–3368) vs. 1778s (1493–2365), P = 0.724]. The average INR was 2.5 ± 0.6 when the second sample was taken. The baseline thrombotic status for the NOAC and VKA group was similar [OT 483s vs. 437s P = 0.386; LT 1519s vs. 1490s, P = 0.326]. The was no significant difference in efficacy in between rivaroxaban and dabigatran and both agents prolonged OT (43 vs. 52%, P = 0.651) and reduced LT (22 vs. 56%, P = 0.917). The CHA2DS2VASC score was similar in the NOAC and VKA groups (2.8 ± 1.6 vs. 3.1 ± 2, P = 0.636). Conclusions The mechanism of action is different for NOAC and VKA. Both of them reduce platelet reactivity, evidenced by the prolongation of OT. NOAC, but not VKA, improve endogenous thrombolysis. This novel mechanism of action of NOAC may underpin the superiority of some NOAC in stroke reduction over VKA, but may also contribute to enhanced bleeding profiles.

29 Comparison of Global Thrombotic Status in AF and Coronary Disease

Introduction Patients with myocardial infarction, stroke and renal disease are at increased risk of future cardiovascular thrombotic events, through increased platelet reactivity, usually due to high shear. Patients affected by these conditions also demonstrate impairment of endogenous thrombolysis. In atrial fibrillation (AF), patients are at increased risk of left atrial thrombus formation, but in a low shear environment. Methods Blood samples were tested from healthy volunteers (n = 82), patients with AF (n = 44), stable coronary artery disease (CAD, n = 31). The patients with AF and CAD were taking aspirin, whereas the healthy volunteers were on no antithrombotic treatment.Thrombotic status was assessed using the near-patient automated Global Thrombosis Test (GTT). This allows assessment of thrombogenicity (platelet reactivity) and endogenous thrombolysis. The GTT measures the time (in seconds) required for thrombus formation (occlusion time, OT) and the time required for spontaneous lysis of that thrombus (lysis time, LT). The test is performed on native blood without external agonists no chemical additives Results In AF patients, median OT was 447s (25th–75th % ile 347–555) and LT was 1472s (1145–2121). In CAD patients OT was 353s (300–441) and LT 1654s (1138–2247) and OT in healthy volunteers was 363s (307–418) with LT of 1052s (896–1256). OT was similar in CAD and healthy volunteers (P = 0.468). In AF patients, OT was prolonged in comparison to normal volunteers (P = 0.004) and CAD patients (P = 0.005). LT was similar in CAD and AF patients (P = 0.598) but prolonged in comparison to healthy volunteers (P < 0.0001). Conclusions Platelet reactivity in healthy volunteers was similar to the profile in CAD patients on aspirin treatment, suggesting that aspirin normalisesthe enhanced platelet reactivity to high sheer in CAD patients. In comparison, patients with AF demonstrate reduced platelet reactivity but markedly impaired endogenous thrombolysis. Thus, AF and CAD patients have differing platelet reactivity, but both demonstrate impairment of endogenous thrombolysis.