Thrombo-Inflammation: A Focus on NTPDase1/CD39

Abstract

There is increasing evidence for a link between inflammation and thrombosis. Following tissue injury, vascular endothelium becomes activated, losing its antithrombotic properties whereas inflammatory mediators build up a prothrombotic environment. Platelets are the first elements to be activated following endothelial damage; they participate in physiological haemostasis, but also in inflammatory and thrombotic events occurring in an injured tissue. While physiological haemostasis develops rapidly to prevent excessive blood loss in the endothelium activated by inflammation, hypoxia or by altered blood flow, thrombosis develops slowly. Activated platelets release the content of their granules, including ATP and ADP released from their dense granules. Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 dephosphorylates ATP to ADP and to AMP, which in turn, is hydrolysed to adenosine by ecto-5'-nucleotidase (CD73). NTPDase1/CD39 has emerged has an important molecule in the vasculature and on platelet surfaces; it limits thrombotic events and contributes to maintain the antithrombotic properties of endothelium. The aim of the present review is to provide an overview of platelets as cellular elements interfacing haemostasis and inflammation, with a particular focus on the emerging role of NTPDase1/CD39 in controlling both processes.

Keywords: ADP; ATP; CD39; CD73; COVID-19; adenosine; inflammation; platelets; thrombosis.

Figure 1

NTPDase1/CD39 and vascular inflammation. After tissue damage, levels of extracellular ATP strongly increase, contributing to boost inflammation, and together with ADP promote platelet activation and aggregation (red lines). Endothelial cell CD39 by hydrolysing ATP to ADP and to AMP, reduces ADP concentrations at the site of injury. CD73 then hydrolyses AMP to adenosine, that inhibits platelet aggregation and reduces inflammation (green lines), providing to maintain tissue homeostasis.

Figure 2

Targeting NTPDase1/CD39 in thrombosis. (A) Recombinant soluble CD39 (solCD39) [39,53,94] through its ATPase and ADPase activities inhibits ADP-mediated platelet activation and aggregation. (B) CD39, fused with a single-chain antibody (scFv) specific for GPIIb/IIIa [94,95,96], expressed on activated platelets, contributes to reduce ADP concentration, providing strong anti-thrombotic effects. (C) The glycoprotein VI (GPVI)Fc-fusion protein is combined to soluble CD39 [97]. The GPVI-Fc inhibits the interaction of GPVI expressed on platelets with vascular collagen in plaques while CD39 reduces the concentrations of ATP/ADP, resulting in a strong inhibition of platelets adhesion and aggregation.