Immune responses to SARS-CoV2 cause activation of platelets, resulting in thrombosis, which can be ameliorated by re-purposed drugs

严重的新冠肺炎感染与肺部和其他器官中血块的形成有关，这会危险地损害它们的功能，并导致这种疾病的死亡。血小板是损伤后触发血液凝固的血细胞，虽然血小板功能异常与血栓形成有关，但这些细胞在触发新冠肺炎相关凝血方面的作用尚不确定。在这项研究中，我们将确定血小板功能的变化是否伴随着疾病的进展和恢复。新冠肺炎患者的严重症状与夸大的炎症反应有关。我们假设这会导致肺血管内凝血的激活。重要的是，凝血和炎症的控制涉及到血小板和免疫细胞中类似的过程和蛋白质，涉及的分子可能是通过设计来控制免疫反应的药物来控制的。我们的初步实验揭示了一种机制，可以解释为什么一些患者似乎特别容易受到新冠肺炎感染的严重影响，而另一些患者相对不受影响。抗体重病患者体内形成的病毒出现异常(病理性抗体)。这些刺激增强了免疫细胞功能，从而可能引发血管炎症。重要的是，我们发现这些抗体还能刺激增强的血小板凝集。这项研究将与正在进行的临床试验结合在一起，以测试改变药物用途的好处，这些药物旨在通过抑制对调节血小板功能也很重要的酶蛋白来针对严重感染中出现的病毒过度活跃的炎症反应。重要的是，我们已经证明了在我们的试验中有一种药物，福斯塔替尼，针对的是病理性抗体对血小板的影响，并防止它们促进血小板凝结。因此，我们将评估与接受标准治疗的患者相比，针对这些抗体影响的药物是否会降低患者的血小板功能，并检查这些新治疗方法的潜在好处是否与血小板功能下降有关。这项研究的结果将确定是否异常的血小板功能是威胁生命的COVID病理背后的原因，以及使用针对血小板和对病毒的免疫反应的药物是否提供了有希望的治疗选择。如果成功，药物再利用将有可能对患者的预后产生快速影响。

Severe COVID-19 infection is associated with the formation of blood clots in the lungs and other organs which dangerously compromise their functions and contribute to mortality of this disease. Platelets are blood cells that trigger blood clotting following an injury, and while abnormal platelet function is associated with thrombosis, the role of these cells in triggering COVID-19-associated clotting is uncertain. In this study we will determine whether changes in platelet function accompanies disease progression and recovery. The serious symptoms suffered by COVID-19 patients are associated with an exaggerated inflammatory response. We hypothesise that this leads to activation of clotting within the blood vessels of the lungs. Importantly the control of clotting and inflammation involves similar processes and proteins within platelets and immune cells involving molecules that may be controlled using drugs that have been designed to control immune responses. Our preliminary experiments have revealed a mechanism which may explain why some patients appear to be particularly predisposed to serious effects of COVID-19 infection while others are relatively unaffected. Antibodies again the virus formed in seriously ill patients appear to be abnormal (pathological antibodies). These stimulate enhanced immune cell function, which may initiate inflammation of blood vessels. Importantly, we have found that these antibodies also stimulate enhanced platelet clotting. This study will be incorporated with an ongoing clinical trial to test the benefits of repurposing drugs that are designed to target the over-active inflammatory response to virus seen in severe infection through inhibiting enzyme proteins that are also important for the regulation of platelet function. Importantly, we have shown that one drug in our trial, fostamatinib, targets the effects of pathological antibodies on platelets, and prevents them from enhancing platelet clotting. We will therefore assess whether drugs that target the effects of these antibodies reduce platelet function in patients, in comparison with patients receiving standard treatments, and examine whether potential benefits of these new treatments are associated with diminished platelet function. The outcomes from this study will establish whether abnormal platelet function lies behind life-threatening COVID pathology, and whether use of drugs that target both the platelet and immune responses to the virus offer promising therapeutic options. If successful, drug repurposing would offer the potential for rapid impact on patient outcomes.