Treatment of spontaneous intracerebral haemorrhage with tranexamic acid

Spontaneous intracerebral haemorrhage is a devastating condition with high morbidity and mortality. Haematoma expansion and subsequent secondary brain injuries lead to worse outcomes in intracerebral haemorrhage. Tranexamic acid is a promising haemostatic agent that may prevent haematoma expansion and improve outcomes. The current thesis explores the effects of tranexamic acid in intracerebral haemorrhage from clinical, radiological and biochemical aspects, based on data from the now completed Tranexamic acid in IntraCerebral Haemorrhage-2 (TICH-2) trial. Two systematic reviews explore available evidence on efficacy and safety of tranexamic acid and other haemostatic therapies in intracerebral haemorrhage. There was insufficient evidence to support the routine use of tranexamic acid or blood clotting factors in treating intracerebral haemorrhage. Platelet transfusion had been found to be harmful and should be avoided in intracerebral haemorrhage. Predictors of neurological deterioration and seizures and the effects of tranexamic acid on both were explored. Older age, more severe stroke, larger haematoma volume, intraventricular and subarachnoid extension, previous intracerebral haemorrhage and antiplatelet therapy independently predicted neurological deterioration. Tranexamic acid reduced early neurological deterioration occurring within 48 hours from symptom onset through a reduction in haematoma expansion, but had no significant effect on late neurological deterioration (48 hours to 7 days). Lobar location of haematoma was the strongest predictor of early (≤ 7 days) and late seizures (> 7 days). The risk of seizures in intracerebral haemorrhage was not increased in patients treated with tranexamic acid. The role of several noncontrast CT signs, namely blend sign, black hole sign, hypodensities and island sign, in predicting haematoma expansion and poor functional outcome was assessed. Blend sign, black hole sign and hypodensities independently predicted haematoma expansion while black hole sign, hypodensities and island sign predicted poor functional outcome (modified Rankin Scale of 4 to 6). Tranexamic acid reduced haematoma expansion but there was no benefit on functional outcome. There was no significant interaction between the presence of noncontrast CT signs and benefit from tranexamic acid in terms of reduction in haematoma expansion or improvement in functional outcome From a biochemical aspect, a range of plasma biomarkers involved in fibrinolysis and haemostasis were examined in a single-centre substudy of the TICH-2 trial involving 22 patients and 9 healthy volunteers. Patients with intracerebral haemorrhage had higher D-dimer and plasmin-alpha-2-antiplasmin complex levels compared to healthy controls. Elevated baseline tissue-type plasminogen activator and urokinase-type plasminogen activator, lower baseline plasminogen and elevated day 2 matrix metalloproteinase-9 levels were associated with haematoma progression. Tranexamic acid did not have significant effects on plasma biomarker levels. In summary, there were clinical and radiological signals that tranexamic acid may be beneficial in patients with spontaneous intracerebral haemorrhage. Plasma biomarker results suggest fibrinolysis may be a pathophysiological mechanism in intracerebral haemorrhage. There is a role for further trials of tranexamic acid in intracerebral haemorrhage