In-vivo Thrombus Imaging With 18F-GP1, a Novel Platelet PET Radiotracer

Cardiovascular thrombotic conditions were estimated to account for 1 in 4 deaths worldwide in 2010 and are the leading cause of global mortality. Divided into arterial and venous thromboses, ischaemic heart disease and ischemic stroke comprise the major arterial thromboses and deep-vein thrombosis and pulmonary embolism comprise the major venous thromboses. Although both arterial and venous thrombi differ in both aetiology and pathophysiology, many commonalities remain.

Thrombosis begins with damage to the vascular wall. Physiological haemostasis is triggered when underlying collagen is exposed to circulating platelets which bind directly to collagen with collagen-specific glycoprotein surface receptors. After an initial signalling cascade involving release of platelet binder von Willebrand Factor, platelets become activated which allows adherence to the site of injury. Following activation, phospholipase A2 modifies the integrin membrane glycoprotein IIb/IIIa (GP IIb/IIIa) increasing platelet ability to bind fibrinogen. The activated platelets then change shape from spherical to stellate, and the fibrinogen cross-links with glycoprotein IIb/IIIa aiding aggregation of more platelets and completing primary haemostasis. Secondary haemostasis involves activation of the coagulation cascade through extrinsic and intrinsic pathways and ends with cross linked fibrin deposition and a mature thrombus.

The haemostatic process is fluid and dynamic with the expression of activated membrane proteins and coagulation factors changing throughout. Platelet expression of GP IIb/IIIa falls as a thrombus matures hence why it is a pharmacological target for antithrombotic therapies. The investigators aim to explore the expression and distribution of GP IIb/IIIa receptors in a range of thrombotic conditions listed below spanning across both arterial and venous systems. Improving understanding of how clinical presentation relates to platelet activation over a range of conditions is crucially important when deciding appropriate anti-thrombotic regimes.

1.2.1 Coronary Heart Disease and Myocardial Infarction Coronary heart disease is the leading cause of death worldwide and is responsible for 17.5 million or 46% of all non-communicable deaths in 2012. The majority of the cardiovascular morbidity and mortality is attributable to coronary atherosclerosis and thrombosis. Atherosclerosis is the central process by which the heart arteries narrow and harden due to the deposition of fatty plaques within the artery wall. This process can result in damage to the lining of the artery which can cause a thrombus (clot) to form within the artery which can partially or completely occlude the flow of blood to the heart muscle thereby precipitating myocardial infarction. This is the commonest form of a heart attack and responsible for a large proportion of sudden cardiac deaths. Thrombus in myocardial infarction is classically thought to be composed of predominantly platelets. However, recent research has shown that 56% of thrombus in MI is composed of fibrin with only 17% platelets. Ischaemic time correlated positively with thrombus fibrin content and negatively with thrombus platelet component. This illustrates the dynamic interaction between platelets and fibrin over time.

1.2.2 Bioprosthetic heart valve thrombosis Bioprosthetic valve thrombosis is an increasingly recognised complication of valve replacement. Patient risks include early prosthesis failure requiring redo operation plus stroke or other systemic embolism. A meta-analysis has estimated the incidence of bioprosthetic thrombosis to be 0.03 per 100 patient years with the risk of embolism being highest in the first 3 months post implantation. The composition of prosthetic valve thrombosis varies depending on valve type and time from insertion. Interestingly in the MISTRAL-C randomised controlled trial, 50% of acute thromboembolic events within 3 days of transcatheter aortic valve insertion were platelet-fibrin thrombus, not calcific debris from the aortic root. Thromboembolism was less common in those on anticoagulant rather than antithrombotic treatment suggesting a fibrin predominance. Similar results were found in a large registry of over 25,000 patients undergoing surgical bioprosthetic valve insertion. Warfarin plus aspirin was more effective than aspirin alone in preventing thromboembolic events and death.