Proposed “COVID-19 Thrombinopathy” cascade and the role of heparins (Preprint)

UNSTRUCTURED Management of life threatening coagulopathy in COVID-19 still remains a clinical challenge. There is still uncertainty regarding the choice and the dose of anticoagulation in Covid-19 coagulopathy especially in critically ill patients. In this article, a new term “COVID-19 thrombinopathy” and a proposed cascade are introduced in order to highlight the non-traditional pathways of thrombin generation which are likely active in COVID-19 (or sepsis), so that the medical community can focus on targeting “thrombin” and “non-traditional thrombin generation” rather than considering general “anticoagulation” based on traditional coagulation pathways. The medical community generalizes unfractionated heparin (UFH) and low molecular weight heparins (LMWH) as “heparins” and also interchanging those in clinical practice. UFH and LMWHs are “heparins” but the targets, therapeutic actions and side effects differ. In addition, during anticoagulation therapy, UFH dosing is based on blood level (therapeutic effect) but LMWH is weight based irrespective of the requirement/underlying clinical condition. Compared to UFH, interestingly and importantly, LMWH has shown to stabilize the clot and make the clot more resistant to breakdown. Preventing platelet activation and its role in traditional and non-traditional thrombogenesis is also essential since it appears to play a major role in COVID-19 thrombinopathy. Further clinical trials are needed to evaluate the benefits of UFH in “COVID-19 thrombinopathy” preferably along with a globally available ADP/P2Y12 blocking anti-platelet agent like Clopidogrel.

EP.WE.690PPI Prescribing in Vascular Discharges

Aims Aspirin and clopidogrel are ubiquitously seen in prescriptions of most attendees to hospitals, especially those being admitted to a vascular unit. Most, if not all, are on at least one anti-platelet agent, and some are on dual antiplatelets (DAPA) or an anticoagulant. These increase the risk for upper gastrointestinal (UGI) bleeds, which lead to significant morbidity and mortality. In order to prevent this, proton pump inhibitors (PPIs) are recommended to be prescribed for patients with increased risk of UGI bleeds. Our aim for this audit was to evaluate the prescription of PPIs in vascular patients discharged from a major vascular hub. Methods Data was collected from a prospectively maintained database of consecutive primary vascular discharges between 01/09/2020 and 31/09/2020. Results 87 patients discharged in this period (71% Male, Median age 72 (22-92) yrs). 26% of admissions accounted for Diabetic foot infection management, 25% for Critical Limb Ischaemia management and 20% for Thoracic or Aortic Aneurysm management. 70% of patients were discharged with either a single or DAPA. 94% of patients met the NICE guideline for requirement for a PPI. 49% of those patients were not discharged with a PPI. Of the patients who should have been prescribed a PPI on discharge, 5% suffered UGI bleeds in the follow up period (2/42). Conclusions PPIs are often not prescribed when discharging vascular patients, most of whom are high risk for having UGI bleeds. We will re-audit this after education and protocols have been implemented.

Effect of anti-coagulation in elderly patients with atrial fibrillation

Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation has been shown to associate with greater cognitive decline and increased dementia risk independent of ischaemic stroke. Anti-coagulation was associated with a lower risk of ischemic stroke and positive net clinical benefit in elderly patients in Asian populations. We hypothesise that elderly patients (>75 years old) with atrial fibrillation on oral anti-coagulants have lower incidence of dementia compared with patients on anti-platelet agents or no anti-thrombotic treatment. Method A retrospective study of 747 patients, male 37%, mean age 84.29 ± 5.99 years old with mean follow up of 13.54 ± 3.38 years. 94 % hypertension, 40% diabetes mellitus, 38% ischaemic heart disease, 33% heart failure, 39% previous stroke, mean CHA2DS2-VASc score of 5.23 ± 1.59. 27% patients on oral anti-coagulants, 64% anti-platelet agent and 9% not on any anti-thrombotic medication. Results 265 patients were diagnosed with dementia, 17 patients were on oral anti-coagulants, 222 patients were on anti-platelet agent. Oral anti-coagulants were associated with lower incidence of dementia compared with anti-platelet agents (p < 0.0001). 26 patients developed dementia were not on any anti-thrombotic agent. 261 patients were readmitted with stroke (2.58%/100 patient year) 182 patients were on anti-platelet agent while 12 were on anti-coagulant (P < 0.0001). Conclusions Oral anti-coagulants were associated with lower incidence of dementia and stroke compared with anti-platelet agents in elderly patients with atrial fibrillation.

Prevention of stroke and dementia in elderly patients with atrial fibrillation

Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation has been shown to associate with greater cognitive decline and increased dementia risk independent of ischaemic stroke. Anti-coagulation was associated with a lower risk of ischemic stroke and positive net clinical benefit in elderly patients. We hypothesise that elderly patients (>75 years old) with atrial fibrillation on oral anti-coagulants have lower incidence of dementia compared with patients on anti-platelet agents or no anti-thrombotic treatment. Method A retrospective study of 747 patients, male 37%, mean age 84.29 ± 5.99 years old with mean follow up of 13.54 ± 3.38 years. 94 % hypertension, 40% diabetes mellitus, 38% ischaemic heart disease, 33% heart failure, 39% previous stroke, mean CHA2DS2-VASc score of 5.23 ± 1.59. 27% patients on oral anti-coagulants, 64% anti-platelet agent and 9% not on any anti-thrombotic medication. Results 265 patients were diagnosed with dementia, 17 patients were on oral anti-coagulants, 222 patients were on anti-platelet agent. Oral anti-coagulants were associated with lower incidence of dementia compared with anti-platelet agents (p < 0.0001). 26 patients developed dementia were not on any anti-thrombotic agent. 261 patients were readmitted with stroke (2.58%/100 patient year) 182 patients were on anti-platelet agent while 12 were on anti-coagulant (P < 0.0001). Conclusions Oral anti-coagulants were associated with lower incidence of dementia and stroke compared with anti-platelet agents in elderly patients with atrial fibrillation.

A retrospective analysis of the factors associated with increased risk of readmission within 30 days following primary transurethral resection of bladder tumour

Background Transurethral resection of bladder tumour (TURBT) is associated with a perioperative morbidity of 5-10% which can lead to unplanned readmissions. In this study, we aim to identify factors that lead to an increased risk of unplanned readmissions within 30 days of primary TURBT. Methods A retrospective study was conducted to identify patients who had their primary TURBT at our institute from 2011-2019. The clinico-demographic factors, history of smoking, intake of anti-platelet drugs, co-morbidities, tumour size (< 3 cm or > 3cm), multifocality and histopathological type were abstracted. The patients who had a readmission were identified and reasons for admission were recorded. Results A total of 435 patients were identified. The median age was 66 years. There were 378 (86.9%) males, 110 (25.3%) had history of smoking and 37 (8.5%) had history of intake of an anti-platelet agent. In the cohort 166 (38.2%) were diabetic, 239 (54.9%) were hypertensive, 72 (16.6%) had COPD, 78 (7.9%) had hypothyroidism. A total of 206 (47.4%) had a tumour of >3cm, multifocality was seen in 140 (32.2%) while muscle invasive tumour was present in 161 (37%) patients. A total of 22 (5.06%) had re-admissions within 30 days with hematuria being the commonest etiology. On the univariate and multivariate analysis, history of smoking ( p=0.006 and 0.008, respectively) or intake of anti-platelet agents (p<0.001 and <0.001, respectively) were significantly associated with increased unplanned readmission. Conclusion Our study revealed smoking and intake of anti-platelet agents as the factors leading to increased risk of unplanned readmissions.

Predictors of intra-procedural stent thrombosis (IPST) during percutaneous coronary intervention (PCI): a pooled data analysis

Background Among all PCI related intraprocedural thrombotic events, IPST is rare but associated with worst outcomes. Purpose We conducted this study to identify specific patient and procedural characteristics that are associated with higher incidence of IPST. Methods Data on patient and procedural characteristics from all the studies comparing IPST without IPST was pooled for the purpose of analysis. Results 5 studies with a total of 21251 patients were included. IPST occurred in 170 patients (0.8%). History of a prior PCI (assumed to be on dual or single anti-platelet agent)was associated with decrease in IPST. IPST occurred more in smokers, patients with abnormal cardiac enzymes at presentation, presentation with STEMI. Incidence of IPST was significantly higher in interventions involving left main artery or bifurcation or with bare metal stent placement. A low pre-TIMI flow of 0 or 1, baseline thrombus, not using upstream GpIIb inhibitors also significantly increased incidence of IPST. Conclusion Further studies are needed to validate above described patient and procedural risk factors. Using upstream GpIIb inhibitors in this specific high-risk population may help in prevention. Funding Acknowledgement Type of funding source: None

Self nano emulsifying solid of clopidogrel - developement, characterization, evaluation and effect on bioavailability

The aim of the present study is the development and characterization of self-nano emulsifying drug delivery systems (SNEDDSs) to improve the rate of dissolution of poorly water-soluble anti-platelet agent clopidogrel bisulfate. The solubility was estimated in various vehicles to select proper components and compositions. Cinnamon oil (as oil), Tween 80 (as a surfactant), polyethylene glycol 400 (as co-surfactant) and Water is used to construct pseudo-ternary phase diagrams. Stability, dispersibility and robustness to dilution were performed to optimize formulations by using the phase diagram. Formulations were prepared with different composed of cinnamon oil, Tween 80 and PEG 400 (Smix) ratios. The globule size of the optimized system was less than 200 nm, which could be an accepted nanoemulsion size range. The selected formulation F 7 SNEEDS of z-average size was 140.8 nm, and zeta potential was -28.6. In vitro, drug release studies showed a significantly enhanced rate of dissolution of F 7 SNEDDS when compared to the marketed formulation.

In Vitro Reversal of the Anti-Aggregant Effect of Ticagrelor Using Untreated Platelets

Background Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined. Methods and Results Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and > 90% reversal at 24 hours. Conclusion Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.