The differential effect of oral anticoagulant types on the coagulant phenotype of vascular endothelium.

Stroke is a leading cause of death and disability. It is the second most common cause of death worldwide, with more than 100,000 strokes in the UK each year, causing 38,000 deaths and an estimated socioeconomic cost to UK society of £26 billion per year. There are two major subtypes of stroke: haemorrhagic (bleeding into brain), accounting for 17% and ischemic (occlusion of blood supply to brain), accounting for 83% of cases.

The occlusion in ischaemic stroke is usually caused by a blood clot forming inside the circulation, frequently on the surface of damaged or inflamed blood vessels. Antiphospholipid syndrome (APS) is an important example of a disease causing an increased risk of ischemic stroke. In APS, antibodies bind to the endothelial cells lining the blood vessel and increase the risk of blood clots.

Because of its serious consequences, current therapies use blood thinning medications (anticoagulants) and drugs that prevent aggregation of platelets (antiplatelet agents) for the prevention of ischaemic stroke. However, these drugs work in several different ways and differ in their efficacy and safety for the treatment of stroke. An important and underappreciated fact which may explain these differences is that the drugs all have different effects on the lining of the vessels as well as the circulating blood.

In health, the endothelium presents an anticoagulant surface which helps maintaining blood in a fluid state by expressing and secreting factors that modulate blood clotting. Accumulated data have demonstrated that damage to the blood vessel wall is driven by chronic low-grade inflammation. It is also clear that the effect of inflammation on the endothelial cells is for them to lose their anticoagulant surface and instead present a surface that promotes blood clotting.

All the currently used anticoagulant drugs will inhibit the blood coagulation mechanisms, but their effect on the endothelial cells will almost certainly differ.

For example, the vitamin K antagonist (VKA) warfarin has been an established and effective anticoagulant for preventing both arterial and venous thrombosis over many years. Warfarin works by its effect on the liver's ability to make blood clotting factors, but it can also influence the production of proteins in the blood vessel wall; although this is not usually considered or measured.

The new direct acting oral anticoagulants (DOACs) have a direct inhibitory effect on blood clotting and may affect the cell response to inflammation but have no direct effect on the ability of endothelial cells to make proteins.

These differences may be of significant clinical importance. Recent studies have shown that in some arterial diseases DOACs are much less effective in preventing stroke than is warfarin. Moreover, in some studies one of the DOACs, dabigatran, produced a relative increase in coronary artery disease. This is despite all the drugs being similarly effective in preventing blood clots in veins.

We hypothesise that although the oral anticoagulants have similar effects on the clotting factors in the blood, they have different effects on endothelial function and the way endothelial cells respond to inflammation.

We propose to investigate and define these differences using a number of approaches already established in our laboratories. Specifically, we will study the formation of blood clots on the surface of normal of inflamed endothelial cells (EC) in the presence and absence of oral different anticoagulants. We will also determine how sticky the surface of the cells become and how readily they trap blood cells (platelets) from flowing blood on their surface.

Finally, we will assess how these effects differ in patients with APS by stimulating EC using antibodies isolated from these patients. The data from these studies will help identify the optimum targets for new therapies and to individualise therapies for specific patients and specific disorders.