Osita Okafor

Endogenous Fibrinolysis: An Important Mediator of Thrombus Formation and Cardiovascular Risk.

Most acute cardiovascular events are attributable to arterial thrombosis. Plaque rupture or erosion stimulates platelet activation, aggregation, and thrombosis, whilst simultaneously activating enzymatic processes that mediate endogenous fibrinolysis to physiologically maintain vessel patency. Interplay between these pathways determines clinical outcome. If proaggregatory factors predominate, the thrombus may propagate, leading to vessel occlusion. However, if balanced by a healthy fibrinolytic system, thrombosis may not occur or cause lasting occlusion. Despite abundant evidence for the fibrinolytic system regulating thrombosis, it has been overlooked compared with platelet reactivity, partly due to a lack of techniques to measure it. We evaluate evidence for endogenous fibrinolysis in arterial thrombosis and review techniques to assess it, including biomarkers and global assays, such as thromboelastography and the Global Thrombosis Test. Global assays, simultaneously assessing proaggregatory and fibrinolytic pathways, could play a role in risk stratification and in identifying impaired fibrinolysis as a potential target for pharmacological modulation.

Allopurinol as a therapeutic option in cardiovascular disease.

ABSTRACT Epidemiological studies indicate that hyperuricaemia is an independent risk factor for cardiovascular disease. Alongside uric acid formation, increased xanthine oxidase activity also results in the formation of oxidative free radicals and superoxide particles. Oxidative stress significantly contributes to the development of cardiovascular disease, including endothelial cell dysfunction, atherosclerosis, vascular calcification and impaired myocardial energetics. Allopurinol, a competitive xanthine oxidase inhibitor, in addition to reducing serum uric acid levels, can act as a free radical scavenger. Although traditionally used for the management of gout, there has been renewed interest in the role of allopurinol in the management of cardiovascular disease. In this review, we summarise the role of the xanthine oxidase pathway in the generation of oxidative stress and evaluate the current body of evidence assessing the clinical effects of allopurinol in patients with cardiovascular disease. A number of small clinical studies have shown a beneficial effect of allopurinol in reducing ischemia‐reperfusion injury in the setting of bypass surgery and coronary angioplasty. Additionally, studies in heart failure indicate a potential favourable effect of allopurinol on endothelial dysfunction, LV function and haemodynamic indices, particularly in those with raised serum uric acid levels. Whilst this cheap and readily available pharmacological option may offer a very cost effective therapeutic option, large‐scale prospective studies are required to better delineate its role in reducing hard clinical end‐points.

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.

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

CHA2DS2VASC SCORE DOES NOT CORRELATE WITH THROMBOTIC STATUS IN ATRIAL FIBRILLATION

The CHA2DS2VASc score is established and recommended for the risk stratification of stroke in patients with atrial fibrillation (AF) based on clinical parameters. How this relates to haematological characteristics, in particular global thrombotic status is unknown. We assessed the thrombotic status

59 Does CHA²DS²VASc Score Correlate with Point-of-Care Global Thrombotic Status in Atrial Fibrillation Patients?

Background The CHA²DS²VASc score is established and recommended for the risk stratification of stroke in patients with atrial fibrillation (AF) based on clinical parameters. How this relates to haematological characteristics, in particular global thrombotic status is unknown. Methods We assessed the thrombotic status of 80 patients with newly diagnosed AF (61% male, 72 ± 12 yrs), who were divided into 3 groups according to CHA²DS²VASc score (Group I: 0–1, Group II: 2–3, Group III: ≥4). Assessment of thrombotic status was performed using the Global Thrombosis Test (GTT), an automated, point-of-care test that assesses both platelet reactivity and endogenous thrombolysis from a native, non-anticoagulated blood sample. The time taken to form an occlusive thrombus under high shear stress (occlusion time, OT), and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured at baseline and after being established on stable anticoagulation. Results Overall CHA²DS²VASc score was 2.9 ± 1.7. There were 21 patients in Group I, 29 in Group II, and 30 in Group III. Anticoagulation prolonged OT (419 ± 122s vs. 584 ± 153s; p = 0.00001), and reduced LT (1939 ± 829s vs. 1625 ± 934s; p = 0.03). At baseline, there was no difference between the 3 groups with respect to OT (Group I: 412 ± 98s, Group II: 434 ± 149s, Group III: 408 ± 110s; p = 0.7), or LT (Group I: 1778 ± 537s, Group II: 1879 ± 747s, Group III: 2108 ± 1038s; p = 0.3). Following anticoagulation, OT was similar in the 3 groups (Group I: 561 ± 148s, Group II: 582 ± 155s, Group III: 602 ± 157s; p = 0.7), and LT was also similar (Group I: 1265 ± 846s, Group II: 1734 ± 817s, Group III: 1775 ± 1050s; p = 0.1). There was no difference in the relative change (∆) in OT (Group I: 149 ± 169s, Group II: 148 ± 129s, Group III: 193 ± 126s; p = 0.4) or LT (Group I: -514 ± 1002s, Group II: -117 ± 928s, Group III: -333 ± 1229s; p = 0.4) between the 3 groups in response to anticoagulation. Conclusions The CHA²DS²VASc score does not appear to reflect global thrombotic status either before or after anticoagulation. Whilst the CHA²DS²VASc score is incredibly useful in assessing populations at risk, it may not be an accurate reflection of the underlying thrombotic status of an individual.

160 Are there Differential Effects of the Novel Oral Anticoagulants on Global Thrombotic Status

Background Novel oral anticoagulants (NOAC) are licensed for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). There has been no head-to-head comparison of these agents. The effect of these agents on global thrombotic status, and the relative effects of the different NOACs, is unknown. We aimed to assess the relative and absolute effect of NOACs and warfarin (VKA) on global thrombotic status. Methods We tested the thrombotic profile of 80 patients (61% male, age 72 ± 12 years) with newly diagnosed AF at baseline, and in response to different oral anticoagulant regimens. Patients were anticoagulated with apixaban (n = 20), dabigatran (n = 20), rivaroxaban (n = 20), or warfarin (n = 20). Assessment of thrombotic status was performed using the Global Thrombosis Test (GTT), an automated point-of-care test that assesses both platelet reactivity and endogenous thrombolysis from a native, non-anticoagulated blood sample. The time taken to form an occlusive thrombus under high shear stress (occlusion time, OT), and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured at baseline and after being established on stable anticoagulation. Results Oral anticoagulation increased OT (419 ± 122s vs. 584 ± 153s; p = 0.00001), and reduced LT (1922 ± 820s vs. 1615 ± 936s; p = 0.01). Although all anticoagulant regimens prolonged OT, the relative prolongation of the OT from baseline was lower with apixaban than with other NOACs or VKA (apixaban 94 ± 135s, dabigatran 185 ± 149s, rivaroxaban 199 ± 104s, warfarin 184 ± 149s; p = 0.06). Apixaban reduced LT from baseline (2056 ± 568s vs. 1313 ± 885s; p = 0.003), but no reduction in LT was observed with other NOACs or VKA. Patients in the dabigatran group were younger than in other groups (65 ± 11; p = 0.006), but otherwise the groups were well matched for sex, diabetes, hypertension, platelet count, haematocrit and fibrinogen levels, and CHA²DS²VASc score. Conclusions All oral anticoagulants (OACs) prolong OT. Apixaban causes relatively less prolongation of OT than other OACs and also reduces LT. The relatively small increase in OT with apixaban compared to other OACs may explain the observed lower incidence of GI bleeds in large trials with this agent.