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Title: Fibrin clot properties and clinical outcomes in patients with acute coronary syndrome : an additional therapeutic target?
Author: Sumaya, Wael
ISNI:       0000 0004 7228 599X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Acute coronary syndrome (ACS) results from thrombotic occlusion of an atherosclerotic coronary artery. Platelets are pivotal in arterial thrombosis and, as a result, preventative therapy has focussed on antiplatelet drugs. Currently, dual antiplatelet therapy with aspirin and a P2Y12 antagonist is the recommended treatment following ACS. Newgeneration P2Y12 inhibitors (ticagrelor and prasugrel) offer potent and consistent antithrombotic effect. Despite this, recurrent events remain common. Mechanisms driving those events are not entirely clear. The protein arm of coagulation also plays an important role in arterial thrombosis, leading to fibrin formation and stabilisation of thrombus. Although the cellular arm of coagulation may be optimally inhibited with contemporary therapy, the protein arm remains largely unaffected. Adverse fibrin clot dynamics have been associated with vascular conditions and with conditions closely related to worse outcome such as diabetes mellitus (DM). It is, therefore, plausible that adverse fibrin-rich clots that resist lysis are responsible for some of the recurrent events. In my PhD, I have studied fibrin clot properties in 4,354 plasma samples, collected at hospital discharge, and 4,032 plasma samples, collected at 1-month, from ACS patients in the PLATelet inhibition and patient Outcome (PLATO) trial. I found that adverse fibrin clots that resisted lysis at hospital discharge independently predicted the combined outcome of cardiovascular (CV) death and spontaneous myocardial infarction with no association with PLATO-defined major bleeding events. Following resolution of inflammation at 1-month, fibrin clot density (determined by maximum turbidity) was attenuated but fibrin clot lysis potential remained relatively stable, showing consistent relationships with high-risk conditions such as DM, peripheral artery disease and chronic kidney disease. Moreover, increased fibrin density and lysis inefficiency strongly correlated with inflammatory and prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide and growth differentiation factor-15) giving us mechanistic insights into worse outcomes. With the cellular arm effectively targeted by contemporary dual antiplatelet therapy, fibrin lysis inefficiency constitutes a therapeutic target to mitigate the residual risk post ACS. I have also studied the ability of different anticoagulants to modulate fibrin clot properties as a novel approach to establish treatment effects. Fibrin clot lag time appeared sensitive to very low concentrations of rivaroxaban, apixaban and fondaparinux and high concentrations promoted fibrinolysis. Therefore, fibrin clot lag time seems promising as a novel assay to monitor treatment but ex-vivo studies are needed to confirm these findings. In an attempt to optimise antithrombotic therapy in ACS patients, I have investigated enoxaparin infusion in ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty as a novel approach to mitigate acute thrombotic risk. Absorption of oral P2Y12 inhibitors is delayed in opiate-treated STEMI patients and this may constitute a risk for acute stent thrombosis. In 20 patients undergoing primary angioplasty, a novel regimen consisting of a bolus of enoxaparin 0.75 mg/kg followed by an infusion of 0.75 mg/kg/6 hours offered sustained anti-Xa levels and improved fibrin clot lysis potential throughout the infusion. No patient suffered a thrombotic complication despite a high prevalence of poor P2Y12 inhibition in opiate-treated patients. This study offers preliminary pilot data to support the hypothesis that this regimen would be sufficient to circumvent the delayed onset of action of oral P2Y12 inhibitors.
Supervisor: Storey, Robert ; Ajjan, Ramzi Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available