Well known trauma drug shows promise for patients with stroke
Dr Zikou Liu
Monash scientists have found that treatment with the anti-fibrinolytic drug, tranexamic acid (TXA), in a mouse model of cerebral amyloid angiopathy blocked plasmin generation, but did not increase amyloid beta deposition over the long-term. Published in the journal, Research and practice in Thrombosis and haemostasis, the findings move the field one stop closer to a candidate secondary stroke prevention therapy for patients with cerebral amyloid angiopathy.
Dr Zikou Liu, lead author of the translational study and early career research fellow in the Molecular Neurotrauma Hemostasis Lab (led by Professor Robert Medcalf) at the Australian Centre for Blood Diseases, said, “Tranexamic acid, or TXA, is generally safe but mostly used in the short term for one day or a week. However, patients with cerebral amyloid angiopathy needing this treatment would need to potentially have it for life to prevent recurrent haemorrhage, so the idea was to test it in the lab to see if it was safe.”
The team randomised the drug TXA or a placebo to a transgenic mouse model - APP/PS1 - an Alzheimer’s like model that accumulates amyloid protein which occurs in cerebral amyloid angiopathy, for six months. “We found that the TXA suppressed plasmin activation, did not increase amyloid beta plaques and importantly did not exacerbate neurological dysfunction,” said Dr Liu. This demonstrates that TXA is a safe candidate secondary stroke prevention therapy for CAA-related stroke, offering new hope for patients who are diagnosed with the condition.
Cerebral amyloid angiopathy is one of the common causes of intracerebral haemorrhage, or stroke, in the secondary care setting. Professor Geoffrey Cloud, a stroke physician and group leader of the Stroke research group in the Department of Neuroscience, and Director of the Stroke Service at Alfred Health said, “Around 12% of all strokes in Australia are caused by bleeding within the brain tissue, also known as intracerebral haemorrhage, of which almost half relate to cerebral amyloid angiopathy or CAA. The advent of MRI has provided great benefit in terms of helping clinicians recognise and diagnose CAA but in terms of treatments, there are none. It can be a pretty ‘hollow’ conversation then in the clinic with patients when this diagnosis of CAA is discussed.”
Back in 2021, Professor Cloud and Professor Robert Medcalf published an opinion piece in the journal Stroke, in which they proposed a novel potential mechanism for cerebral amyloid angiopathy-related intracerebral haemorrhage involving the fibrinolytic (clot-busting) system and the need for randomised clinical trials to test their hypothesis.
“It is known in the fibrinolysis field that amyloid can drive plasmin generation in the same way as fibrin can – proteins in the fibrinolysis systems including amyloid and fibrin, are all cleared by the same mechanism,” said Professor Robert Medcalf.
A protein called amyloid beta is usually cleared away through perivascular spaces of the brain. However, in cerebral amyloid angiopathy it accumulates and deposits within the vessel walls of the brain. As cerebral amyloid angiopathy progresses, injury and a loss of compliance to the vessel walls occurs. Plasmin, an important enzyme in the blood, is produced when the fibrinolysis system is activated by amyloid beta. This can lead to an increased permeability in the blood brain barrier, inflammation and unstoppable bleeding or stroke, fatal in severe cases.
“There is a huge unmet need for treatment of CAA as it is becoming increasingly recognised as a major cause of haemorrhagic stroke. We are now designing a 3 month safety and feasibility study using oral tranexamic acid in patients who have suffered symptomatic brain haemorrhage due to CAA and hope to start recruiting in 2024, which is very exciting,” said Professor Cloud.
Dr Liu has presented the study in a “research recap online session” for the International Society for Thrombosis and Haemostasis, moderated by Professor Beverley Hunt, an international expert in thrombosis and haemostasis at King’s College in London.
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Source:
Liu, Z., McCutcheon, F. M., Ho, H., Chia, J., Xiao, Y., Tippett, I., Keragala, C. B., Cloud, G. C., & Medcalf, R. L. (2023). Tranexamic acid in a mouse model of cerebral amyloid angiopathy: setting the stage for a novel stroke treatment approach. Research and practice in thrombosis and haemostasis, 7(6), 102166. https://doi.org/10.1016/j.rpth.2023.102166
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