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

中风是导致死亡和残疾的主要原因。中风是世界上第二大最常见的死亡原因，英国每年有超过10万例中风，导致3.8万人死亡，据估计，英国社会每年的社会经济成本为260亿英镑。中风有两种主要亚型：出血性（脑出血），占17%；缺血性（脑供血阻塞），占83%。缺血性中风的闭塞通常是由血液循环内形成的血块引起的，通常是在受损或发炎的血管表面。抗磷脂综合征（APS）是导致缺血性中风风险增加的疾病的一个重要例子。在APS中，抗体与血管内皮细胞结合，增加血栓的风险。由于其严重后果，目前的治疗方法使用血液稀释药物（抗凝剂）和防止血小板聚集的药物（抗血小板药物）来预防缺血性卒中。然而，这些药物以几种不同的方式起作用，在治疗中风的疗效和安全性上也存在差异。可能解释这些差异的一个重要但未被充分认识的事实是，所有药物对血管内壁和循环血液都有不同的影响。在健康状态下，内皮呈现出一种抗凝表面，通过表达和分泌调节血液凝固的因子，帮助维持血液处于液体状态。积累的数据表明，血管壁的损伤是由慢性低度炎症引起的。同样清楚的是，炎症对内皮细胞的影响是使它们失去抗凝表面，而呈现出促进血液凝固的表面。目前使用的抗凝药物都有抑制凝血的机制，但它们对内皮细胞的作用几乎肯定是不同的。例如，维生素K拮抗剂（VKA）华法林多年来一直是一种有效的抗凝剂，用于预防动脉和静脉血栓形成。华法林的作用是影响肝脏产生凝血因子的能力，但它也会影响血管壁蛋白质的产生；虽然这通常不被考虑或衡量。新的直接作用口服抗凝剂（DOACs）对血液凝固有直接抑制作用，可能影响细胞对炎症的反应，但对内皮细胞制造蛋白质的能力没有直接影响。这些差异可能具有重要的临床意义。最近的研究表明，在一些动脉疾病中，DOACs在预防中风方面的效果远不如华法林。此外，在一些研究中，一种doac，达比加群，导致冠状动脉疾病的相对增加。尽管所有的药物在预防静脉血栓方面都同样有效。我们假设，尽管口服抗凝剂对血液中的凝血因子有相似的作用，但它们对内皮功能和内皮细胞对炎症反应的方式有不同的影响。我们建议使用我们实验室已经建立的一些方法来调查和定义这些差异。具体来说，我们将研究在口服不同抗凝剂存在和不存在的情况下，正常炎症内皮细胞（EC）表面血栓的形成。我们还将确定细胞表面的粘性如何，以及它们如何容易地从表面流动的血液中捕获血细胞（血小板）。最后，我们将通过使用从APS患者中分离的抗体刺激EC来评估这些效果在APS患者中的差异。来自这些研究的数据将有助于确定新疗法的最佳靶点，并针对特定患者和特定疾病进行个性化治疗。

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.