The only medical therapy proven to be effective in acute stroke is reperfusion of the brain using tissue plasminogen activator (tPA; alteplase). This treatment is strongly endorsed by Australian and international guidelines. However, although up to 40% of cases are eligible, no more than 7% are actually receiving treatment. One of important reasons for this poor uptake is the adverse drug event termed haemorrhagic transformation of infarction. One in 20 people treated with tPA develop clinically significant haemorrhagic transformation (HT) that can result in death or serious disability. Currently there are no proven strategies to predict, prevent or effectively treat these patients; the risk factors and the pathophysiology of HT are poorly understood. Given the success of pharmacogenomics in explaining the basis of many other adverse drug events, we propose that a similar line of inquiry will shed light on !PA-associated HT.
In this study of the Genetics of !PA-associated HT, (the GotH study) we will investigate which genetic variants are associated with an increased risk of HT. We will build on the national and international links established through previous and current NHMRC grants to prospectively recruit a cohort of !PA-treated stroke patients, with and without HT. The top signals identified in a genome-wide association study (GWAS) in Australian and US cases will then be specifically replicated in an independent cohort of international cases. The study addresses an issue of major importance in acute stroke care: why do some people bleed following the use of thrombolytic therapy and what are the determinants of this
serious adverse event?