Evaluation of the mechanisms of hemostatic activation in COVID-19 and their modulation by bradykinin inhibitors

Abstract

Severe forms of COVID-19 are characterized by intense inflammation associated with significant increase in biomarkers of hemostasis activation. According to the concept of immunothrombosis, hemostasis and inflammation are intimately connected elements of the host response to pathogens. Based on this model, when regulated, local activation of hemostasis contributes to pathogen eradication, but when deregulated or with loss of localization, it can lead to secondary damage, such as the formation of thrombi in the microcirculation. Interestingly, the activation of hemostasis during inflammation is apparently mediated by different pathways that those activated in response to breaches in endothelial line causing post-traumatic bleeding, and involves elements such as the expression of tissue factor in monocytes and microparticles, the activation of intrinsic pathways by DNA released from neutrophil extracellular traps, among others. In addition, endothelial barrier disruption, which also contributes to the host's response to injury by mediating diapedesis, can become a secondary mechanism of injury, by promoting changes in the alveolar-capillary barrier or even to the activation of hemostasis. In this project, we will evaluate a panel of laboratory parameters linked to the activation of hemostasis and to the regulation of endothelial barrier integrity in patients with COVID-19 enrolled in a clinical study aimed to evaluate the effect of bradykinin inhibitors on the clinical course of this disease. The panel will be performed at different time-points (admission, days +4, +12 and +28), and the allocation by treatment groups will allow us to assess these parameters in patients on supportive treatment, or under use of bradykinin inhibitors, which have the potential to modulate both the crosstalk between inflammation and the intrinsic coagulation pathway, and the regulation of endothelial barrier integrity. (AU)