Medicine (Northern Health) - Theses
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ItemPeri-Operative Myocardial Injury and Type 2 Myocardial Infarction( 2023-04)This thesis explores the major themes of Peri-Operative Myocardial Infarction and Injury (PMI), and Type 2 Myocardial Infarction (T2MI), both entities where understanding of pathophysiological mechanisms and clinical presentation and management are not completely understood and continuing to evolve (1, 2). PMI could be either T2MI, Type 1 Myocardial Infarction (T1MI), or Myocardial Injury, where T1MI refers to an acute plaque rupture and thrombus formation. T2MI on the other hand refers to an oxygen supply-demand mismatch to the myocardium, precipitated by a variety of potential factors, with or without underlying stable coronary plaque (3). Both PMI and T2MI are commonly encountered in a hospital in-patient setting, following non-cardiac surgery and precipitant other medical conditions respectively (4-6). Pivotal to the diagnosis of both is the measurement of cardiac troponin, and the other major thread to this body of work is the impact that the relatively new high-sensitivity troponin assays have had to the landscape of these conditions clinically, and to our understanding of them pathophysiologically (7). There are currently no proven, specific interventions that reduce cardiovascular risk in patients undergoing non-cardiac surgery (8, 9). The incidence of PMI is substantial, in the order of 30% for all non-cardiac surgery (10-12). In this setting, there is a great need for specific interventions that can reduce this incidence in patients at risk - this is the basis for the world-first, prospective, double-blind randomised multicentre placebo-controlled trial that is part of this thesis, which investigates a first-in-class drug Ivabradine in preventing PMI in an elderly population undergoing orthopaedic surgery for acute fracture. T2MI accounts for the majority of troponin elevations in a hospital population, and has similar if not worse prognosis to T1MI (13-15). However, the diagnosis, investigation, and management of T2MI at the bedside in any given patient is not always clear. Determining the likely pathophysiological process based on clinical information alone in some cases may be difficult, and there is a thought that the newer high-sensitivity troponin assays may exacerbate this. The broad aims of this body of work are: 1. To better understand the pathophysiological mechanisms of PMI and T2MI, in particular the role of increased heart rate 2. To investigate an intervention with Ivabradine started pre-operatively to reduce the risk of PMI, in a setting where there are currently no proven therapies. 3. To evaluate determinants and risk factors for PMI and T2MI in specific clinical contexts, and investigate long-term outcomes after PMI. 4. To explore the effect of the new high sensitivity troponin assay on all of the above, in particular the clinical diagnosis and landscape of both PMI and T2MI. We achieved the above aims through the following methods: 1. A world-first, prospective, double-blind, randomised, multicentre placebo-controlled trial investigating a novel use of the first-in-class drug Ivabradine. 2. A world-first prospective case series using intra-coronary Optical Coherence Tomography (OCT) imaging in an inpatient T2MI population. 3. A large-scale retrospective analysis of an entire tertiary hospital’s experience in the transition to the new high sensitivity troponin assay from a standard assay, focused on all T2MI relative to all T1MI. REFERENCES 1. Mauermann E, Puelacher C, Lurati Buse G. Myocardial injury after noncardiac surgery: an underappreciated problem and current challenges. Current opinion in anaesthesiology. 2016;29(3):403-12. 2. Helwani MA, Amin A, Lavigne P, Rao S, Oesterreich S, Samaha E, et al. Etiology of Acute Coronary Syndrome after Noncardiac Surgery. Anesthesiology. 2018. 3. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018;138(20):e618-e51. 4. Liem VGB, Hoeks SE, Grune F, Mol K, Wesdorp F, Stolker RJ, et al. Prognostic value of postoperative high-sensitivity troponin T in patients with different stages of kidney disease undergoing noncardiac surgery. British journal of anaesthesia. 2018;120(1):84-93. 5. Puelacher C, Lurati Buse G, Seeberger D, Sazgary L, Marbot S, Lampart A, et al. Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, Mortality, and Characterization. Circulation. 2017. 6. Collinson P, Lindahl B. Type 2 myocardial infarction: the chimaera of cardiology? Heart (British Cardiac Society). 2015;101(21):1697-703. 7. Chong CP, van Gaal WJ, Savige J, Lim WK. Cardiac injury and troponin testing after orthopaedic surgery. Injury. 2011;42(9):855-63. 8. Hoshijima H, Denawa Y, Mihara T, Takeuchi R, Kuratani N, Mieda T, et al. Efficacy of prophylactic doses of intravenous nitroglycerin in preventing myocardial ischemia under general anesthesia: A systematic review and meta-analysis with trial sequential analysis. Journal of clinical anesthesia. 2017;40:16-22. 9. Devereaux PJ, Duceppe E, Guyatt G, Tandon V, Rodseth R, Biccard BM, et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet (London, England). 2018;391(10137):2325-34. 10. Ollila A, Vikatmaa L, Virolainen J, Vikatmaa P, Leppaniemi A, Alback A, et al. Perioperative Myocardial Infarction in Non-Cardiac Surgery Patients: A Prospective Observational Study. Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society. 2017;106(2):180-6. 11. Toda H, Nakamura K, Nakagawa K, Watanabe A, Miyoshi T, Nishii N, et al. Diastolic Dysfunction Is a Risk of Perioperative Myocardial Injury Assessed by High-Sensitivity Cardiac Troponin T in Elderly Patients Undergoing Non-Cardiac Surgery. Circulation journal : official journal of the Japanese Circulation Society. 2018;82(3):775-82. 12. Bass AR, Szymonifka JD, Rondina MT, Bogardus M, Scott MG, Woller SC, et al. Postoperative Myocardial Injury and Inflammation Is Not Blunted by a Trial of Atorvastatin in Orthopedic Surgery Patients. HSS journal : the musculoskeletal journal of Hospital for Special Surgery. 2018;14(1):67-76. 13. Chapman AR, Adamson PD, Mills NL. Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart (British Cardiac Society). 2017;103(1):10-8. 14. Smilowitz NR, Naoulou B, Sedlis SP. Diagnosis and management of type II myocardial infarction: increased demand for a limited supply of evidence. Current atherosclerosis reports. 2015;17(2):478. 15. Sandoval Y, Smith SW, Thordsen SE, Apple FS. Supply/demand type 2 myocardial infarction: should we be paying more attention? Journal of the American College of Cardiology. 2014;63(20):2079-87.
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ItemGlobal coagulation assays as predictive biomarkers in thrombotic disease( 2023-08)Venous thromboembolism (VTE) continues to be a leading cause of morbidity and mortality globally. As was evident during the COVID-19 pandemic, thrombosis also exacerbates a number of inflammatory illnesses through the mechanism of ‘thrombo-inflammation’. Predicting thrombotic complications continues to be a major challenge in the management of VTE and other thrombo-inflammatory diseases. Though efforts have been made to find biomarkers that can enhance our capacity to risk-stratify thrombotic risk, none have yet been successfully adopted clinically. Better predictive biomarkers are required to personalise anticoagulant medication such that thrombotic consequences in high-risk persons are minimised and low-risk individuals are not exposed to unnecessary bleeding risk. In this thesis, we explore the use of global coagulation assays (GCAs), in particular the overall haemostatic potential (OHP) assay, modified by a lower concentration of thrombin trigger (0.003U/mL) as a predictive biomarker in VTE, post-thrombotic syndrome (PTS) and COVID-19. We reviewed our local experience using D-dimer as a predictive biomarker for VTE recurrence. Although high D-dimer was shown to be correlated with increased risk of VTE recurrence, there were important drawbacks including poor specificity, a high rate of VTE recurrence in individuals who test negative for D-dimer, and the requirement to test off anticoagulation. Next, we described variations of fibrin generation and fibrinolysis in health controls, as determined by the OHP assay. Age >50 years and female sex was associated with high fibrin generation capacity and lower fibrinolytic capacity. Current predictive biomarkers for VTE recurrence require testing after a period of anticoagulation withdrawal. We demonstrate that OHP assay retains predictive ability for VTE recurrence, even in the presence of therapeutic anticoagulation, and outperformed D-dimer. Similarly, high OHP>13 units during therapeutic anticoagulation was an independent predictor of progression to PTS (OR 2.17, 95%CI 1.06-4.43, p=0.03). This was incorporated into a multivariate prediction model for PTS, with a c-statistic of 0.77. Pulmonary microthrombi and abnormal fibrin deposition in the alveoli have been implicated in the pathogenesis of severe COVID-ARDS. Using residual plasma collected in 2022 Omicron patients at hospital admission, we found high OHP >20 units to be an independent predictor of oxygen requirement (OR 3.23, 95%CI 1.52-6.86, p=0.002). A multivariate prediction model incorporating OHP was constructed with excellent c-statistic of 0.86. Finally, we show that DOAC-stop can be used to remove the in-vitro interference of DOACs and allow thrombin generation assays to be performed even in anticoagulated individuals, meaning thrombin generation results can now be evaluated as a predictive biomarker without stopping anticoagulation. Overall, we have shown the OHP assay to be a comprehensive global coagulation assay with promising predictive potential in VTE, PTS and COVID-19. Future research may expand its application to other thrombo-inflammatory diseases and combine multiple global coagulation assays with other novel biomarkers, to better model the coagulation sequence and refine thrombotic risk stratification.
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ItemGlobal coagulation assays in health and disease( 2022)Thrombosis is a major global cause of morbidity and mortality, and predicting the risk of thrombotic and cardiovascular complications remain a challenge in modern medicine. Clinical surrogate markers and conventional coagulation testing, which only measures the time to start of clot formation, do not sufficiently predict individual risks. Global coagulation assays (GCA), which includes the assessment of the final products of the coagulation cascade, namely thrombin and fibrin, may be helpful adjunctive tools. Whilst GCAs have been more widely investigated in bleeding states, their role in thrombotic disorders is less well-established. In this thesis, we investigated the use of GCAs such as thromboelastography (TEG), calibrated automated thrombogram (CAT) and overall haemostatic potential assay (OHP) in healthy controls and a variety of disease states. These included thrombocytopenia and hypercoagulable states such as diabetes mellitus, plasma cell dyscrasia, the influence of hormone status, particularly oestrogen (transgender women on oestradiol therapy) as well as in coronavirus (COVID-19). We described the effect of basic demographic characteristics in healthy controls, particularly age and gender, on GCAs. Female controls demonstrated more hypercoagulable TEG and CAT parameters while age appeared to influence TEG, but not CAT parameters. Interestingly, healthy controls with “flattened” thrombin curves were associated with worse cardiovascular risk profile, possibly attributable to increased TFPI, suggesting a degree of compensation within the coagulation system in response to endothelial activation. Despite the common association of thrombocytopenia with bleeding, quantitative platelet counts do not always accurately predict this risk and thrombosis can occur despite thrombocytopenia. We reported while markedly thrombocytopenic patients demonstrated hypocoagulable profiles, patients with mild thrombocytopenia paradoxically appeared to have more hypercoagulable parameters. Overall, GCAs demonstrated the ability to help clinicians further discriminate thrombocytopenic patients. There is significant heterogeneity in the incidence and severity of diabetes-associated vascular complications, with limitations to clinical surrogate risk factors and glycated haemoglobin (HbA1c) as risk stratifiers. In addition to diabetes being a hypercoagulable state, particularly on TEG and OHP, we found several parameters to be associated with increased risk of diabetic complications and proposed a prediction model using a combination of GCA parameters (C-statistic 0.82). This is of clinical and prognostic significance as it may have utility in detecting early vascular complications and provide an indicator for early intervention. A larger prospective study with long-term follow-up of patient outcomes is ongoing. Monoclonal gammopathy of unknown significance (MGUS) is considered the clinically asymptomatic precursor of multiple myeloma although both forms are associated with an increased thrombotic risk. Contrary to expectations, there were no significant differences in the GCA parameters between patients with multiple myeloma and its MGUS precursor. However, patients who had arterial thrombotic events during the follow-up period demonstrated hypofibrinolysis based upon the OHP parameters. In exploring the role of hormonal influences on GCAs, we found that transgender women on oestradiol therapy demonstrated hypercoagulable TEG and CAT parameters as well as increased fibrinolysis compared to cisgender males. There was no significant difference seen relative to cisgender females, reflecting the shift towards feminisation. The route of estradiol delivery, its duration of use or the presence of concurrent anti-androgen therapy did not influence the GCA parameters. It is now well established that COVID-19 patients are susceptible to coagulopathy and thrombotic complications. We demonstrated marked impairment of fibrinolysis in COVID-19 patients compared to healthy controls and septic patients. Furthermore, patients with markedly increased OHP were more likely to require intensive care admission and ventilatory support. This suggests fibrinolysis may be an important therapeutic target in the management of one of the most challenging conditions we have faced in a century. Overall, we have shown that GCA appear to provide an advantage over conventional coagulation assays in the assessment of haemostatic function. While there are still limitations impeding the general applicability of these assays, further technical improvements may facilitate their introduction into clinical practice. Our data also suggest that these assays may have clinical utility in refining the thrombotic risk stratification. Further larger prospective studies to validate these findings are warranted.