Platelets and SARS-CoV-2 During COVID-19: Immunity, Thrombosis, and Beyond

Abstract

COVID-19 is characterized by dysregulated thrombosis and coagulation that can increase mortality in patients. Platelets are fast responders to pathogen presence, alerting the surrounding immune cells and contributing to thrombosis and intravascular coagulation. The SARS-CoV-2 genome has been found in platelets from patients with COVID-19, and its coverage varies according to the method of detection, suggesting direct interaction of the virus with these cells. Antibodies against Spike and Nucleocapsid have confirmed this platelet-viral interaction. This review discusses the immune, prothrombotic, and procoagulant characteristics of platelets observed in patients with COVID-19. We outline the direct and indirect interaction of platelets with SARS-CoV-2, the contribution of the virus to programmed cell death pathway activation in platelets and the consequent extracellular vesicle release. We discuss platelet activation and immunothrombosis in patients with COVID-19, the effect of Spike on platelets, and possible activation of platelets by classical platelet activation triggers as well as contribution of platelets to complement activation. As COVID-19-mediated thrombosis and coagulation are still not well understood in vivo, we discuss available murine models and mouse adaptable strains.

Keywords: COVID-19; SARS-CoV-2; cell death; platelets; thrombosis.

Figure 1.

Transmission electron micrographs (TEMs) of platelets incubated with SARS-CoV-2 or from a patient with COVID-19. Platelets were incubated with infectious SARS-CoV-2 (WA strain; alpha variant); control represents the media in which the virus was eluted post purification. TEMs show release of cytoplasmic content post membrane rupture that, in general, is the last step of lytic programmed cell death in nucleated cells. These TEMs suggest signaling beyond classical platelet activation. Figure is borrowed from Koupenova et al (Figure 5 and Figures S2 and S4) and is copyright of AHA Journals (CircRes).

Figure 2.

Platelet activation during COVID-19 and contribution to thrombosis. Various classical platelet agonists become available as a result of the infected environment. Among these are ATP and ADP (adenosine diphosphate) released from dying, infected or damaged cells. ATP (not shown in the figure) is also quickly converted to ADP. TF (tissue factor) generated by damaged vessels and epithelial cells can lead to thrombin (IIa) generation by the extrinsic coagulation cascade. ADP and IIa can act on their respective receptors on platelets: ADP on P2Y12 and P2Y1 and IIa on PAR1 and PAR4. The result is increased granule release and consequent P-selectin and CD154 surface expression leading to interaction with leukocytes (heterotypic aggregation [HAG]) in addition to increased activation of the fibrinogen receptor, α2bβ3 (GPIIb/IIIa or CD41/CD61) leading to increased adhesion and aggregation. Additionally, platelet-monocyte HAGs lead to increased TF expression in monocytes, further contributing to the coagulation potential of the environment. These processes can be controlled by antiplatelet drugs. In addition to the response to environmental cues, platelets can also internalize the virus partially through ACE2 (angiotensin-converting enzyme 2) and partially by picking up microparticles with attached virions. Viral RNA in platelets can then initiate programmed cell death pathways in platelets leading to Casp3 activation, MLKL (Mixed Lineage Kinase Domain Like Pseudokinase) phosphorylation and consequently to extracellular vesicle release. Phosphorylated MLKL can oligomerize and form pores on the surface leading to intracellular content release. Molecules such as S100A8/A9, generally located in the cytoplasm of cells, can then be released in the environment. Extracellular vesicles and S100A8/A9 can lead to endothelial damage which further amplifies thrombosis and coagulation. Casp3 activation can lead to PS (phosphatidyl serine) surface translocation on platelets. Platelets with translocated PS, and perhaps EVs with PS on their surface can provide the surface for increased coagulation. It is unclear if classical platelet agonists have an effect on the response of platelets in their direct interaction with the virus. Illustration credit: Ben Smith.

Figure 3.

Platelets from COVID-19 patients vary in size. Consistent with the reported increased mean platelet volume (MPV), we find platelets bigger than 5 µm. We also find platelets smaller than 2 µm proposing a loss of platelet content that may be attributed to activation of programmed cell death pathways. Figure is borrowed from Koupenova et al and is copyright of AHA Journals (CircRes).