Thrombosis.

The Thrombosis Group is internationally renowned for its innovative research into blood clot formation and factors, which can exacerbate development of pathological clots, leading to heart attacks and stroke. Our findings go a long way to explaining why the drugs we currently administer to patients with cardiovascular disease – which target the blood-borne chemicals – don’t always work.

What impact will this research have?

Atherothrombosis is a major healthcare problem in Australia, affecting more than 50 per cent of the adult population. We’re hoping to develop innovative approaches to reduce the risk of blood clot in patients and ultimately save lives.

Current projects and goals

Research undertaken in our laboratory is focussed on determining the mechanisms underlying clot formation in healthy individuals; using this knowledge to better understand the mechanisms leading to platelet hyperactivity and pathological blood clot formation;and ultimately development of safer and more effective therapies to treat cardiovasuclar diseases including heart attack, stroke, diabetes and the metabolic syndrome.

“Bad Blood”: Unravelling the Link between Gut Ischemia and Remote Organ Injury

Ischaemic injury to vital organs is common in critically ill patients, producing deleterious effects on other organ systems. This is particularly common in the gut, with intestinal hypoperfusion inducing systemic inflammation and multiorgan organ dysfunction syndrome. In addition to promoting inflammation, prolonged ischemic injury to the intestines can also lead to the development of a systemic thrombotic response (pathological formation of blood clots), which is particularly common in the lung, and leads to a very poor prognosis (>90% mortality). Recent studies from our laboratory have identified a new mechanism of pathological blood clotting (thrombosis) and vascular occlusion that is triggered by dying platelets in the intestinal microvasculature. Our ultimate aim is to identify new therapeutic targets to improve microvascular perfusion and reduce inflammation and organ injury, which may represent an innovative approach to reduce remote organ injury in critically ill patients.

Solving a sticky clotting problem in Diabetes

The leading cause of death in diabetes is cardiovascular disease, with up to 70% of deaths relating to the development of blood clots supplying the heart (heart attack) or brain (ischemic stroke). Diabetic individuals are more prone to develop blood clots, and these clots are more resistant to standard anticlotting therapies. Our laboratory has discovered a new clotting mechanism severely affected by diabetes that is resistant to the beneficial effects of commonly used antithrombotic agents, including aspirin, clopidogrel and warfarin. Studies currently ongoing in our laboratory aim to identify how high blood sugar levels (hyperglycaemia) can enhance this new clotting mechanism. To achieve this, we are using Biomembrane force probe (‘BFP’) technology recently established at the Charles Perkins Centre (CPC), University of Sydney. This platform is the first of its kind in Australia, and allows us to study how a single platelet senses mechanical cues at the molecular scale.
 

New approaches to the treatment of ischaemic stroke

The development of a blood clot in the cerebral circulation (ischaemic stroke) is the third most common cause of death and the most common cause of adult disability globally. The central goal of stroke therapy is the prompt reperfusion of occluded blood vessels to minimise tissue death. The delivery of fibrinolytic agents modelled on tissue-type plasminogen activator (t-PA) is the only clinically approved means available to stroke patients. Despite this, the use of t-PA is associated with significant side-effects, limiting its widespread use. We are working on a novel approach to improve upon existing stroke therapies, making them safer and more effective. Ongoing studies using a novel mouse model of thrombolysis (iCAT) developed in our lab will determine whether cerebral damage and cognitive impairment associated with stroke are reduced using this approach.

Investigating novel regulators of platelet procoagulant activity – targeting safer anticoagulation

Antithrombotic therapies, which primarily consist of anti-platelet and anticoagulant agents, have become the cornerstone therapies for a wide variety of cardiovascular diseases. All currently employed anticoagulant agents indiscriminately inhibit coagulation reactions at the injured vessel wall and throughout the body of a developing blood clot, increasing bleeding risk for patients receiving these medications. Recent progress in understanding the mechanisms by which platelets can support blood coagulation suggest that selective inhibition of “platelet-specific” procoagulant pathways may reduce thrombin generation within a blood clot, potentially providing a novel and safer approach to reducing blood clotting. Our laboratory has recently defined an important role for the necrotic cell death pathway in partially regulating platelet procoagulant function, and ongoing studies will investigate alternative processes regulating this response. We will determine whether therapeutic targeting of these pathways srepresent a safe and effective way of reducing thrombin generation in vivo without increasing bleeding risk.