PB0594 - Hypercoagulability in COVID-19 and its putative association with the downregulation of protein C signalling

Background: Hematological complications associated with prothrombotic events with extrapulmonary manifestations have been demonstrated in autopsies of patients affected by coronavirus disease 2019 (COVID-19). Based on the close relationship of coagulation and immune response, we hypothesized that hypercoagulability in COVID-19 could result from the activation of tissue factor (F3) and subsequent alterations in Activated Protein C (APC) signaling (Figure 1).

Aims: We aimed to identify changes in the expression of APC signaling network in liver, peripheral blood and nasal epithelium of COVID-19 patients that may contribute to local and systemic disarrangement of hemostasis.

Methods: For the expression of PROC and receptor genes public single-cell-RNA-sequencing datasets were analyzed from COVID-19 patients and healthy individuals, using the toolkit Scanpy 1.7.2 in Phyton.

Results: The key compounds of Protein C (PC) activation and signaling; PROCR, F2R, THBD, S1PR1 and PROC were downregulated in COVID-19 patients; a greater expression of F3 in all COVID-19 tissues analyzed and upregulation of AGTR1, NFKB1, PTPN1, THBS1, PTGS2, PLAU, SERPINE1 and F5 pro-inflammatory and procoagulant genes in the liver of COVID-19 patients compared to control (Figure 2B, E and G). The hepatocyte PROC expression was changed in COVID-19 patients from hepatocyte 4 ADH1B+ PCK1+ in healthy liver (Figure 2F) to hepatocyte 3 CYP2A6+ in the liver of COVID-19 patients (Figure 2A). The ACE2 expression was increased in all COVID-19 tissues (Figure 2B, E and G) overlapping the PROC expression in the epithelium (Figure 2D) and liver tissues (Figure 2A). There was a co-expression of ACE2, PROC, PROS1, RHOA, and RAC1 in ciliated cells of COVID-19 patients (Figure 2C-D).

Conclusion(s): The results provide evidence indicating a deficient synthesis and activation of PC and its receptors in COVID-19 patients that might contribute to a pronounced hypercoagulable state in response to endothelial COVID-19- related injury. Financial support: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).