Fig. 3

Platelet receptor/signaling and COVID-19. Low platelet level in some patients with COVID-19 can be due to massively activated platelets. Platelets contain alpha, delta, T, and lysosomal granules. VAMPs may mediate platelet endocytosis. Fibrinogen normally imports into the platelet α-granules and is fused with vWF. Platelets have various receptors: integrins; GP Ib/IX/V; TLRs; thrombin receptors of PAR-1 and PAR-4; ADP receptor of P2Y12; GPVI. In viral infections, TLRs are activated that cause the secretion of complement C3 from alpha granules in platelets. They also release GM-CSF. Complement C3 and GM-CSF stimulate NETosis. SARS-CoV-2 pathogenesis indirectly induces an enhanced capability of VWF to bind to its receptors on platelets. VWF binds to GPIb-IX-induced transient platelet adhesion. Thrombin is another ligand for GPIb-IX. It stimulates the PKG and MAPK pathway and, ultimately, granule secretion. GPVI is known as a collagen receptor. In this pathway, PIP2 hydrolyzes into DAG and IP₃ by PLC2 mediation. DAG and IP₃ are known as secondary messengers. DAG activates PKC isoforms. PKCs are involved in integrin activation and platelet granule secretion. IP₃ increases calcium concentration in cytosol of cells by affecting the dense tubular system channel. Calcium elevation is also required for stable platelet adhesion, granule secretion, procoagulant activity, and clot retraction and collectively almost all platelet functions. PAMPs and DAMPs (such as HMGB1) bind to PRRs, such as TLRs. They prompt platelet activation. TLRs activate PLC2. They also activate the PKG pathway. Minimally three thrombin receptors on human platelet surface have been defined, i.e., GPIb-IX, PAR1, and PAR4. GPIb-IX signaling plays a pivotal role in the assembly of NOX subunits and ROS production. It can also activate PLC through a ROS-mediated signaling pathway. Then, PLC activation leads to DAG and IP₃ formation, which has already been described. PAR1 and PAR4 also activate PLC isozymes and have an effect on the PKG and MAPK pathway. Integrins are also important platelet molecules involved in platelet activity, adhesion, and aggregation, including collagen, fibronectin, etc. They are substantial for the stable adhesion and aggregation of platelets. COVID-19, coronavirus disease 2019; GP Ib/IX/V, glycoprotein, Ib/IX/V; TLRs, Toll-like receptors; GM-CSF, granulocyte–macrophage colony-stimulating factor; C3, complement component 3; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; PKG, protein kinase G; vWF, von Willebrand factor; MAPK, mitogen-activated protein kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; DAG, 1,2-diacylglycerol; IP₃, 1,4,5-trisphosphate; PKC, protein kinase C; PLC2, phospholipase C-2; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PRRs, pattern recognition receptors