Medicine (Northern Health) - Theses

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    Global coagulation assays as predictive biomarkers in thrombotic disease
    Wang, Jue ( 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.