Coming safely to a stop : a review of platelet activity after cessation of antiplatelet drugs

Funding Isobel Ford is an employee of the University of Aberdeen. The research for the writing of this review received no specific grant from any funding agency in the public, commercial, or not-forprofit sectorsPeer reviewedPostprin

Thrombin-anti-thrombin levels and patency of arterio-venous fistula in patients undergoing haemodialysis compared to healthy volunteers : a prospective analysis

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Platelet function in patients with end-stage renal failure undergoing haemodialysis

Background: The onset of thrombosis in the vascular access for dialysis has a significant impact on access survival, quality of life and health care cost. Controversy exists as to the role of platelet activation in vascular access thrombosis. We aimed to assess platelet activity in patients on haemodialysis (HD) compared with healthy volunteers. Methods: Venous blood samples were taken from 55 patients immediately before (baseline) and 30 min after HD and from 72 resting healthy volunteers. Platelet function was assessed by: (1) Ultegra rapid platelet function assay (RPFA), using the agonists thrombin receptor activating peptide (TRAP) and arachidonic acid (ASA), and (2) flow cytometric measurement of P-selectin expression and fibrinogen binding both with and without ex vivo 10 uM ADP stimulation. Results: At baseline, ASA-stimulated platelet aggregation was lower in patients on aspirin (n = 27) compared with volunteers (median (iqr) 471 (82) versus 650 (54), P 0·05). TRAP-stimulated platelet aggregation was not significantly different between patients and volunteers. P-selectin expression on unstimulated platelets was lower in patients than volunteers (% positive platelets 0·79 (1·0) versus 1·68 (1·43), P < 0·001). Fibrinogen binding on resting platelets was higher in patients than volunteers [median (IQR) 1·95 (0·99) versus 1·39 (0·75) P < 0·001] but ADP-stimulated fibrinogen binding was lower [40·9 (25·8) versus 50·6 (19·8]. Following HD, there were no significant changes in ASA aggregation, unstimulated P-selectin or fibrinogen binding. Changes in TRAP-aggregation, stimulated P-selectin and fibrinogen binding occurred post-dialysis. The effects of heparin could contribute to some of the post-HD changes. Conclusion: This study suggests a complex picture of platelet function, but no overall evidence of increased platelet activation in patients on haemodialysis. Although aspirin might be required for its cardioprotective role, it may not aid the prevention of access thrombosis. Other causes and preventative medical therapies for vascular access thrombosis require to be investigated.peer-reviewe

Double-blind randomized placebo-controlled trial of the antiplatelet effects of aspirin-clopidogrel combination versus aspirin alone at endovascular intervention for intermittent claudication of the lower limb

Intermittent claudication is a common problem which causes significant impairment of quality of life and increased mortality. Endovascular recanalization, widely used for symptomatic relief, carries a high risk of reocclusion. Platelets play a central role in this process. Aspirin currently used in claudicants reduces the risk, and more potent antiplatelet strategies may reduce this further. The aim of this study was to investigate the antiplatelet effect of aspirin–clopidogrel versus aspirin alone in patients with claudication undergoing endovascular intervention. Methods: This was a double-blind randomized placebo-controlled trial; 132 patients were randomized to clopidogrel and aspirin or to placebo and aspirin with a loading dose 12 h before endovascular intervention. Flow cytometric measurement of platelet fibrinogen binding and P-selectin expression as measures of platelet activation status and of platelet responsiveness to stimulation at baseline, 12 h post-loading dose, 1 h, 24 h and 30 days postintervention. Results: Platelet activation was significantly diminished in the clopidogrel group at 12 h post-loading dose compared to baseline (P-selectin: 27·3 per cent reduction, P = 0·017; bound fibrinogen: 34·7 per cent reduction, P = 0·024; stimulated bound fibrinogen: 49 per cent, P < 0·001). No significant change was observed in the control group. Platelet function was significantly suppressed in the clopidogrel group at 1 h, 24 h and 30 days after endovascular intervention compared to the placebo group (P < 0·001). Conclusion: Clopidogrel–aspirin combination dramatically inhibits platelet function in claudicants before and after intervention. The combination treatment may help reduce reocclusion after endovascular recanalization.peer-reviewe

Clopidogrel has no effect on D-dimer and thrombin-antithrombin III levels in patients with peripheral arterial disease undergoing peripheral percutaneous transluminal angioplasty

Objective: Coagulation activation markers are significantly elevated in patients with peripheral arterial disease compared with healthy controls. The more severe the disease, the higher the markers. Increased coagulation activation may contribute to the disease process and the risk of complications in patients with peripheral arterial disease, particularly after endovascular intervention. Animal studies have shown that clopidogrel significantly inhibits coagulation activation. The aim of this study was to determine whether combination of aspirin and clopidogrel affects thrombin-antithrombin III and D-dimer in patients with intermittent claudication undergoing angioplasty, compared with aspirin alone. Methods: This was a double blind, randomized placebo-controlled trial conducted in a vascular unit in a tertiary referral center. One hundred thirty-two patients with intermittent claudication were randomized to clopidogrel and aspirin or placebo and aspirin, with a loading dose 12 hours before endovascular intervention. D-dimer and thrombin-antithrom- bin III (TAT) levels were measured using enzyme-linked immunosorbent assay at baseline, 1 hour before, and 1 hour, 24 hours, and 30 days after intervention in 103 patients who underwent endovascular intervention. Results: There was a significant rise in D-dimer levels at 1 hour and 24 hours after angioplasty in both groups (placebo group: 63.69, 141.45, 122.18 ng/mL; clopidogrel group: 103.79, 159.95, 134.69 ng/mL), but no difference between the two groups (P .514). Similarly there was a significant rise in TAT levels at 1 hour after angioplasty in both groups (placebo group: 2.93, 6.16 g/L; clopidogrel group: 3.39, 5.27 g/L), with no significant difference between the two groups (P .746). Conclusion: Endovascular intervention results in a significant increase in TAT and D-dimer. The addition of clopidogrel to aspirin has no effect on TAT and D-dimer before or after endovascular intervention.peer-reviewe

Markers of coagulation activation, endothelial stimulation and inflammation in patients with peripheral arterial disease

Objectives. Patients with peripheral arterial disease have a significantly increased risk of cardiovascular and cerebrovascular mortality. Studies have shown that some haemostatic and inflammatory markers are elevated in these patients but the effect of the severity of the disease has not been fully documented. The aim of this study was to assess the level of coagulation activation, endothelial stimulation and inflammation in patients with claudication and critical limb ischaemia (CLI) compared to healthy controls. Design and methods. A prospective observational study was conducted amongst 202 subjects: 132 claudicants, 30 patients with critical ischaemia, and 40 controls. D-dimer (DD) and thrombin–antithrombin III (TAT) levels measured using ELISA as markers of coagulation activation. von Willebrand factor (vWF) and high-sensitivity C-reactive protein (CRP) levels were measured as markers of endothelial and inflammatory stimulation. Results. vWF and CRP levels were significantly higher in patients with intermittent claudication (1.9 U/ml, range 0.78– 4.05; p!0.001; 3.4 mg/l, range 0.15–24; pO0.001, respectively) and critical ischaemia (2.36 U/ml; range 1.03–5.69; p! 0.001; 7.17 mg/ml, range 0.15–174; p!0.001, respectively) compared to controls (1.28 U/ml, range 0.62–3.13; 1.04, range 0.15–7.59 mg/l). DD was also significantly higher in claudicants (48.6 mg/ml; range 2–1741; p!0.001) and in patients with CLI (61.1 mg/ml, range 3.65–1963; p!0.001) compared to controls (26.1 mg/ml, range 9.65–203.1). TAT levels were significantly higher in CLI (3.14 mg/l, range 2.09–58.11), compared to controls (2.36 mg/l, range 1.49–7.38; pZ0.004). Patients with CLI had significantly higher levels of CRP, vWF, and TAT than claudicants. Conclusions. Coagulation activation and endothelial stimulation are significantly increased in patients with peripheral arterial disease compared to healthy controls. Coagulation and endothelial activation increases with the severity of the arterial disease.peer-reviewe

Platelet activation is increased in peripheral arterial disease

Platelet activation was assessed in patients with peripheral arterial disease compared with healthy control subjects. Methods This prospective comparative study included 100 subjects: 40 consecutive patients with intermittent claudication, 20 consecutive patients with critical ischemia and tissue loss, and 40 healthy control subjects. Whole blood flow cytometric analysis was performed to determine resting and stimulated platelet P-selectin expression and resting and stimulated platelet fibrinogen binding. Results are presented as platelet percentage and also as mean fluorescence intensity. Results P-selectin expression was significantly increased in patients with intermittent claudication (median, 0.85%; range, 0.31%-4.77%; P = .023) and critical ischemia (median, 1.11%; range, 0.2%-3.26%; P = .028) compared with control subjects (median, 0.59%; range, 0.16%-4.58%). The percentage of platelets binding fibrinogen was also significantly higher in patients with intermittent claudication (median, 2.89%; range, 1.08%-9.59%; P < .001) compared with control subjects (median, 1.57%; range, 0.17%-10.7%). There was no significant difference in percentage of platelet fibrinogen binding between control subjects and patients with critical ischemia. Fibrinogen binding by stimulated platelets was significantly diminished in patients with critical limb ischemia compared with control subjects (67.2% vs 77.9%; P = .006). Conclusions Platelet activation is increased in patients with peripheral arterial disease, suggesting an underlying prothrombotic state. Platelets from patients with critical limb ischemia are less responsive to in vitro stimulation.peer-reviewe

Activated platelets and coagulation in patients on haemodialysis

Objective: Patients on haemodialysis (HD) have an increased risk of cardiac events. Controversy exists as to whether these patients have a pro-thrombotic state. We aimed to determine markers of platelet activation and coagulation in patients on HD compared with healthy volunteers. Method: Platelet function was assessed in 78 patients pre-HD and 78 volunteers by: i) Ultegra rapid platelet function assay using the agonists thrombin receptor activating peptide (TRAP) and arachidonic acid (ASA); ii) flow cytometry of P-selectin expression and fibrinogen binding with/without ADP stimulation; and iii) measuring plasma soluble P-selectin. Coagulation and fibrinolysis were assessed by ELISA determination of thrombin-antithrombin (TAT) and D- dimer, respectively. Results: ASA-stimulated platelet aggregation was significantly reduced in HD patients, of whom 50 (64%) were on aspirin therapy (median [IQR] 555 [355–671] versus 649 [385–675], p < 0·001). TRAP-mediated aggregation was similar in both groups. Unstimulated fibrinogen binding was significantly increased in patients (2·02 [1·48–2·62] versus 1·46 [1·15–1·94], p < 0·001) but stimulated fibrinogen was decreased (40·75 [26·7–50·3] versus 50·05 [40·6–59·9], p < 0·001). Unstimulated P-selectin was significantly decreased in patients (0·82 [0·52–1·46] versus 1·62 [0·86–2·34], p < 0·001), yet soluble P-selectin was significantly increased (43·26 [13·88–86·7] versus 24·67 [13·41–43·32], p = 0·039). Stimulated P-selectin was similar in both groups. Markers of coagulation were significantly increased in patients on HD: TAT 4·59 (2·67–6·04) versus 2·84 (1·81–3·82), p < 0·001 and D-dimer 876·5 (434·2–1338·5) versus 265·5 (175·0–401·51), p < 0·001. Conclusion: Patients on HD have a pro-thrombotic state with chronically activated platelets and elevated markers of coagulation. Drug therapy to counteract this pro-thrombotic state should be considered with the aim of preventing both cardiac events and vascular access thrombosis.peer-reviewe

Effect of Antiplatelet Therapy (Aspirin + Dipyridamole Versus Clopidogrel) on Mortality Outcome in Ischemic Stroke

The optimal regimen of antiplatelet therapy for secondary prevention in noncardioembolic ischemic stroke remains controversial. We aimed to determine which regimen was associated with the greatest reduction in adverse outcomes. We analysed prospectively collected data from the Norfolk and Norwich University Hospital Stroke Register (NNUHSR). The sample population consisted of 3,572 participants (mean age 74.96 ± 12.67) with ischemic stroke, who were consecutively admitted between 2003-2015. Patients were placed on one of three antiplatelet regimens at hospital discharge; aspirin monotherapy, aspirin plus dipyridamole and clopidogrel. Clopidogrel and aspirin plus dipyridamole was compared to aspirin. A direct comparison between clopidogrel and aspirin plus dipyridamole was also performed. Outcomes included all-cause mortality and a combined endpoint of all-cause mortality and incidence of major adverse cardiac events (stroke or myocardial infarction). Cox-regression models adjusted for potential confounders at the following time periods after discharge; 0-90 days, 91-365 days and 1-3 years. Aspirin plus dipyridamole was associated with a lower risk of mortality at 0-90 days; HR 0.62 (0.43-0.91). Clopidogrel was associated with a lower risk of mortality at 1-3 years; HR of 0.39 (0.26-0.60). Similar HRs were observed for the the corresponding time points in the composite outcome. In conclusion Patients with non-cardioembolic stroke may gain maximum benefit from aspirin plus dipyridamole initially (≤1 year) with a subsequent switch to clopidogrel, with regard to mortality and MACE outcomes

Adapting student practice placements in response to COVID-19: 'Get there together' a digital stories project for people living with dementia

The impact of COVID-19 has been harshly felt by occupational therapists in practice and students requiring practice education placements. A collaboration between Aneurin Bevan University Health Board (ABUHB) and Cardiff University enabled 10 undergraduate students to undertake their final placement by participating in a Digital Stories Project. This placement was innovatively designed to allow students to meet their learning objectives remotely, reducing clinical days in adherence to social distancing measures. The ‘Get There Together’ project was created by the national steering group after identifying the devastating impact COVID-19 had on people affected by dementia when accessing community occupations. The students collaborated with service users to identify areas that they wanted to visit, creating digital recordings explaining what to expect due to COVID-19 rules. This paper will focus on the conception and development of the Digital Stories Project, which helped increase placement capacity for occupational therapy students, during the COVID-19 pandemic